Compositions comprising a delivery agent and preparation thereof

ABSTRACT

The invention relates to granules and pharmaceutical compositions comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a lubricant obtained by mixing hereof for more than 5 minutes prior to granulation as well as processes for their preparation and use thereof in medicine.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.14/386,218, filed Sep. 18, 2014, which is a 35 U.S.C. § 371 NationalStage application of International Application PCT/EP2013/055363 (WO2013/139695), filed Mar. 15, 2013, which claimed priority of EuropeanPatent Applications 12160742.8, filed Mar. 22, 2012 and European PatentApplication 13153422.4, filed Jan. 31, 2013; this application claimspriority under 35 U.S.C. § 119 of U.S. Provisional Application61/748,844; filed Jan. 4, 2013; the contents of all above-namedapplications are incorporated herein by reference.

INCORPORATION-BY-REFERENCE OF THE SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted in ASCII format via EFS-Web and is hereby incorporated byreference in its entirety. Said ASCII copy,“8482US02_SeqListing_ST25.txt”, created on Sep. 16, 2014 and modified onOct. 24, 2018. The Sequence Listing is made up of 2 kilobytes, and theinformation contained in the attached “SEQUENCE LISTING” is identical tothe information in the specification as originally filed. No new matteris added.

BACKGROUND

Pharmaceutical formulations comprising proteins and peptides can bemanufactured from for example granules, which are compressed intotablets, or from blends of granules and excipient(s), which arecompressed into tablets. The granulation process may be carried out as adry granulation process where granules are formed from either blendscontaining excipients or from blends comprising the pharmaceuticalactive ingredient and one or more excipients. Dry granulation may becarried out by compaction of the blend into ribbons in a rollercompactor followed by milling of the ribbons. A dry granulation processmay also be carried out by compression of the blend into tabletsfollowed by milling of the tablets, i.e. slugging.

In dry granulation processes, sticking of material to either the rollsof the roller compactor used for dry granulation or to the die andpunches of the tablet press used to form granules/tablets may preventproper processing resulting in an unacceptable product quality, i.e.granule quality or tablet quality, or in an unacceptable low processyield, or in no processability at all. In order to prevent suchsticking, lubricant(s) are frequently added to the blend. Lubricants maycomprise magnesium stearate, stearic acid, talc, etc. It is well-knownthat lubrication of the blend used for dry granulation is a major causeof decreased mechanical strength and prolonged disintegration time ofthe final compressed tablets. Likewise lubrication of the blend fortablet compression is well known to reduce the mechanical strength ofthe tablets, prolong the disintegration time of the tablets, prolong therelease of the pharmaceutical active ingredient from the tablet andincrease tablet friability. This phenomenon is known asover-lubrication.

Over-lubrication is caused by high concentration of lubricant(s) or bylong mixing time of the lubricant(s) with the remaining ingredients ofthe blend used for either dry granulation or tablet compression.Over-lubrication may be caused by formation of a hydrophobic layeraround powders and/or granules used to manufacture the tablet leading toe.g. slower dissolution and/or poorer wetting and/or reduced bindingproperties. Therefore, the mixing time of the lubricant(s) has to becarefully controlled and kept at a minimum, while keeping theconcentration of lubricant(s) as low as possible to prevent theundesirable effects of over-lubrication.

SUMMARY

In some embodiments the invention relates to a granule comprising a saltof N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a lubricant, whereinthe composition is obtained by mixing said salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic and said lubricant for more than 5minutes prior to granulation.

In some embodiments the invention relates to a process of producing apharmaceutical composition comprising granules comprising a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid and a lubricant, such amagnesium stearate, wherein said process comprises the steps: a) mixingsaid salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and saidlubricant for more than 5 minutes; and b) optionally roller compactingthe mixture of step a.

In some embodiments the invention relates to a pharmaceuticalcomposition obtained by the process as defined herein. In someembodiments the invention relates to a granule obtained by the processas defined herein.

In some embodiments the invention relates to a composition or a granuleas defined herein for use in medicine, such as for treatment of diabetesor obesity. In some embodiments the invention relates to a method fortreatment of diabetes or obesity comprising administering thecomposition or a granule as defined herein.

DESCRIPTION

In some embodiments the present invention relates to tablets preparedfrom a blend of granules and excipients. In some embodiments the term“granule” refers to particles gathered into larger particles. In someembodiments a “granule” is formed by gathering small particles into alarge mass. In some embodiments the term “granulate” refers to severalgranules, such as two or more granules. The granules, which comprise asubstance that promotes the absorption of drugs, were prepared by rollercompaction using a high concentration of the lubricant magnesiumstearate, i.e. 2 to 5% (w/w). The present inventors surprisingly foundthat the mixing time of the lubricant/excipient blend for the granules,which was used for the dry granulation process, had no disadvantageouseffect in terms of reduced mechanical strength of the tablets, prolongeddisintegration time of the tablets or increased tablet friability.Contrary to common general knowledge no or even a beneficial impact ofthe mixing time of the lubricant/excipient blend for the granules on thepharmaceutical technical properties of the tablets were seen, i.e.unaltered or higher crushing strength and unaltered or lower friabilityof the final tablets was obtained.

Likewise, the size of the granules and the extent of granulation weresurprisingly unaffected by changes in the mixing time of thelubricant/excipient blend for the granules.

Accordingly, in some embodiments the present invention provides a largerwindow of time in which the mixing step of the lubricant/excipient blendfor the granules can be performed in the manufacture of tablets withoutdetrimental effects on the tablet properties, such as mechanicalstrength and/or friability.

Pharmaceutical Compositions

In some embodiments the invention relates to a granule comprising a saltof N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a lubricant, whereinthe composition is obtained by mixing said salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic and said lubricant for more than 5minutes prior to granulation. In some embodiments the invention relatesto a pharmaceutical composition comprising a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid and a lubricant, wherein thecomposition is obtained by mixing said salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic and said lubricant for more than 5minutes.

In some embodiments the duration of said mixing is at least 6 minutes,such as at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45 or 50 minutes. Insome embodiments the duration of said mixing is at least 30 minutes orat least 40 minutes, such as at least 50 minutes. In some embodimentsthe duration of said mixing is no more than 12 hours, such as no morethan 10, 8, 6, 4, or 2 hours.

In some embodiments the amount of lubricant is at least 0.25% (w/w) orat least 0.5% (w/w), such as at least 1% (w/w) or at least 2% (w/w), ofsaid composition. In some embodiments the amount of lubricant is no morethan 10% (w/w), such as no more than 8, 7, or 6% (w/w), of saidcomposition. In some embodiments the lubricant is magnesium stearate.

In some embodiments the composition comprises one or morepharmaceutically acceptable excipients. In some embodiments thecomposition comprises a filler, such as microcrystalline cellulose. Insome embodiments the composition comprises a binder, such as povidone.As used herein the term “composition” refers to a pharmaceuticalcomposition.

In some embodiments the composition comprises granules which have beenmanufactured by dry granulation. In some embodiments the compositioncomprises granules which have been manufactured by roller compaction. Insome embodiments the moldings from the roller compactions process arecomminuted into granules.

In some embodiments the composition is in the form of a solid dosageform. In some embodiments the composition is in the form of a tablet. Insome embodiments the composition is in the form of a capsule. In someembodiments the composition is in the form of a sachet.

In some embodiments the composition or granule comprises at least onepharmaceutically acceptable excipient. The term “excipient” as usedherein broadly refers to any component other than the active therapeuticingredient(s). The excipient may be an inert substance, which is inertin the sense that it substantially does not have any therapeutic and/orprophylactic effect per se. The excipient may serve various purposes,e.g. as a delivery agent, absorption enhancer, vehicle, filler (alsoknown as diluents), binder, lubricant, glidant, disintegrant,crystallization retarders, acidifying agent, alkalizing agent,preservative, antioxidant, buffering agent, chelating agent, complexingagents, surfactant agent, emulsifying and/or solubilizing agents,sweetening agents, wetting agents stabilizing agent, colouring agent,flavouring agent, and/or to improve administration, and/or absorption ofthe active substance. A person skilled in the art may select one or moreof the aforementioned excipients with respect to the particular desiredproperties of the solid oral dosage form by routine experimentation andwithout any undue burden. The amount of each excipient used may varywithin ranges conventional in the art. Techniques and excipients whichmay be used to formulate oral dosage forms are described in Handbook ofPharmaceutical Excipients, 6th edition, Rowe et al., Eds., AmericanPharmaceuticals Association and the Pharmaceutical Press, publicationsdepartment of the Royal Pharmaceutical Society of Great Britain (2009);and Remington: the Science and Practice of Pharmacy, 21th edition,Gennaro, Ed., Lippincott Williams & Wilkins (2005).

In some embodiments the composition or granule comprises a filler, suchas lactose (e.g. spray-dried lactose, α-lactose, β-lactose, TABLETOSE®,various grades of PHARMATOSE®, MICROTOSE® or FAST FLO-C®),microcrystalline cellulose (various grades of AVICEL®, ELCEMA®,VIVACEL®, MING TAI® or SOLKA-FLOC®), other cellulose derivatives,sucrose, sorbitol, mannitol, dextrins, dextrans, maltodextrins,dextrose, fructose, kaolin, mannitol, sorbitol, sucrose, sugar, starchesor modified starches (including potato starch, maize starch and ricestarch), calcium phosphate (e.g. basic calcium phosphate, calciumhydrogen phosphate, dicalcium phosphate hydrate), calcium sulphate,calcium carbonate, or sodium alginate. In some embodiments the filler ismicrocrystalline cellulose, such as Avicel PH 101.

In some embodiments the composition or granule comprises a binder, suchas lactose (e.g. spray-dried lactose, α-lactose, β-lactose, TABLETOSE®,various grades of PHARMATOSE®, MICROTOSE® or FAST FLO-C®),microcrystalline cellulose (various grades of AVICEL®, ELCEMA®,VIVACEL®, MING TAI® or SOLKA-FLOC®), hydroxypropylcellulose,L-hydroxypropylcellulose (low-substituted), hypromellose (HPMC) (e.g.Methocel E, F and K, Metolose SH of Shin-Etsu, Ltd, such as, e.g., the4,000 cps grades of Methocel E and Metolose 60 SH, the 4,000 cps gradesof Methocel F and Metolose 65 SH, the 4,000, 15,000 and 100,000 cpsgrades of Methocel K; and the 4,000, 15,000, 39,000 and 100,000 gradesof Metolose 90 SH), methylcellulose polymers (such as, e.g., Methocel A,Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose,ethylcellulose, sodium carboxymethylcellulose, other cellulosederivatives, sucrose, dextrins, maltodextrins, starches or modifiedstarches (including potato starch, maize starch and rice starch),calcium lactate, calcium carbonate, acacia, sodium alginate, agar,carrageenan, gelatin, guar gum, pectin, PEG, or povidone. In someembodiments the binder is povidone, such as Povidone K 90.

In some embodiments the composition or granule comprises a disintegrant,such as alginic acid, alginates, microcrystalline cellulose,hydroxypropyl cellulose, other cellulose derivatives, croscarmellosesodium, crospovidone, polacrillin potassium, sodium starch glycolate,starch, pregelatinized starch, or carboxymethyl starch (e.g. PRIMOGEL®and EXPLOTAB®).

In some embodiments the composition or granule comprises a lubricant,such as stearic acid, magnesium stearate, calcium stearate or othermetallic stearate, talc, waxes, glycerides, light mineral oil, glycerylbehenate, hydrogenated vegetable oils, sodium stearyl fumarate,polyethylene glycols, alkyl sulfates, or sodium benzoate. In someembodiments the composition or granule comprises a lubricant, such asmagnesium silicate, talc, or colloidal silica. In some embodiments thelubricant is magnesium stearate.

In some embodiments the composition or granule comprises one or moreexcipients selected from crystallization retarders, such as Povidone,etc.; solubilizing agents (also known as surfactants), such as anionicsurfactants (e.g. Pluronic or Povidone), cationic surfactants, nonionicsurfactants, and/or zwitterionic surfactants; colouring agents,including dyes and pigments, such as Iron Oxide Red or Yellow, titaniumdioxide, and/or talc; and/or pH control agents, such as citric acid,tartaric acid, fumaric acid, sodium citrate, dibasic calcium phosphate,and/or dibasic sodium phosphate.

In some embodiments the composition comprises one or morepharmaceutically acceptable excipients. In some embodiments thecomposition comprises a filler and/or a binder. In some embodiments thefiller is microcrystalline cellulose. In some embodiments the binder ispovidone. In some embodiments the composition comprises a lubricant. Insome embodiments the lubricant is magnesium stearate.

In some embodiments the composition comprises at least 60% (w/w)delivery agent, less than 10% (w/w) binder, 5-40% (w/w) filler, and lessthan 10% (w/w) lubricant.

In some embodiments the composition comprises at least 60% (w/w), suchas 65-75% (w/w), 60-80% (w/w), or 50-90% (w/w), delivery agent. In someembodiments the composition comprises at least 70% (w/w), such as 70-80%(w/w), delivery agent.

In some embodiments the composition comprises 0.1-10% (w/w), such as0.2-4% (w/w) or 0.5-3% (w/w), binder. In some embodiments thecomposition comprises 1.5-2.5% (w/w), such as 1.7-2.3% (w/w), 1.8-2.2%(w/w), or 1.9-2.1% (w/w), binder. In some embodiments the compositioncomprises 1% (w/w) or 2% (w/w) binder.

In some embodiments the composition comprises 5-40% (w/w), such as10-30% (w/w) or 5-25% (w/w), filler. In some embodiments the compositioncomprises 10-25% (w/w), such as 17-23% (w/w), 18-22% (w/w), or 19-21%(w/w), filler. In some embodiments the composition comprises 10.9% (w/w)or 18% (w/w) filler, or comprises 19.5% (w/w) or 20.5% (w/w) filler.

In some embodiments the composition comprises 0.1-10% (w/w) or 0.5-5%(w/w), such as 1-3.5% (w/w) or 1% (w/w), lubricant. In some embodimentsthe composition comprises 1.5-3% (w/w), such as 2.1-2.7% (w/w), 2.2-2.6%(w/w) or 2.3-2.5% (w/w), lubricant.

Still further, the composition or granule of the invention may beformulated as is known in the art of oral formulations of insulinotropiccompounds.

In some embodiments the invention relates to a pharmaceuticalcomposition comprising a first and a second type of granules. In someembodiments the pharmaceutical composition further comprises anextragranular lubricant, such as magnesium stearate.

In some embodiments the invention relates to a first granule comprisingat least 75% (w/w) delivery agent, less than 10% (w/w) lubricant, andoptionally less than 20% filler and no GLP-1 peptide. In someembodiments the invention relates to a first granule comprising at least80% (w/w) delivery agent, less than 10% (w/w) lubricant, and optionallyless than 20% filler and no GLP-1 peptide. In some embodiments the firstgranule comprises 75-90% (w/w), such as 78-88% (w/w), 80-86% (w/w) or82-84% (w/w), delivery agent. In some embodiments the first granulecomprises less than 10% (w/w), such as 1-3% (w/w), 1.5-2.5% (w/w) or1.9-2.3% (w/w), lubricant, In some embodiments the first granulecomprises less than 20%, such as 10-20% (w/w), 12-18% (w/w) or 14-17%(w/w), filler. In some embodiments the first granule comprises no GLP-1peptide. In some embodiments the granule comprises at least 80% (w/w)delivery agent, less than 10% (w/w) lubricant, and optionally less than20% filler.

In some embodiments the invention relates to a second granule comprisinga GLP-1 peptide, at least 15% (w/w) filler and less than 40% (w/w)binder and no salt of NAC. In some embodiments the second granulecomprises at least 1%, such as 1-70% (w/w), 2-40% (w/w) or 4-30% (w/w),GLP-1 peptide. In some embodiments the second granule comprises at least20%, such as 40-80% (w/w) or 50-75% (w/w), filler. In some embodimentsthe second granule comprises less than 30%, such as 5-30% (w/w), 10-28%(w/w) or 15-25% (w/w), binder. In some embodiments the second granulecomprises no salt of NAC. In some embodiments the granule comprises aGLP-1 peptide, at least 15% (w/w) filler and less than 40% (w/w) binder.In some embodiments the granule comprises at least 60% (w/w) filler andless than 40% (w/w) binder. The composition or granule may beadministered in several dosage forms, for example as a tablet; a capsulesuch as hard capsules, sachet or a powder. The composition or granulemay further be compounded in a drug carrier or drug delivery system,e.g. in order to improve stability and/or solubility or further improvebioavailability. In some embodiments the composition is in the form of asolid dosage form. In some embodiments the solid dosage form is atablet. In some embodiments the composition is in the form of a capsule.In some embodiments the composition is in the form of a sachet.

In some embodiments the weight of the tablet is in the range of 150 mgto 1000 mg, such as in the range of 300-600 mg or 350-450 mg.

Methods of Preparation of Pharmaceutical Compositions

The composition of the invention may be prepared as is known in the art.In some embodiments the composition or the granule may be prepared asdescribed in the examples herein. In some embodiments the compositionmay be granulated prior to being compressed into tablets. In someembodiments the granules of the invention are manufactured by drygranulation, such as by roller compaction compaction. In someembodiments the moldings from the roller compactions process arecomminuted into granules. The composition may comprise one or moreintragranular parts and an extragranular part, wherein the intragranularparts have been granulated, and wherein the extragranular part has beenadded after granulation. A first intragranular part may comprise theGLP-1 peptide and one or more excipients, and a second intragranularpart may comprise the delivery agent and optionally one or moreexcipients. A first intragranular part may comprise the GLP-1 peptide,filler and/or a binder and a second intragranular part may comprise thedelivery agent, lubricant and/or filler. In some embodiments the firstintragranular part comprises the GLP-1 agonist (i.e. the GLP-1 peptide),microcrystalline cellulose and/or povidone and the second intragranularpart comprises the delivery agent, magnesium stearate and/ormicrocrystalline cellulose. The extragranular part may comprise alubricant. In some embodiments the extragranular part comprisesmagnesium stearate. In some embodiments the filler and/or a binder is afiller or and filler and a binder.

To prepare a dry blend of tabletting material, the various componentsare weighed, optionally delumped and then combined. The mixing of thecomponents may be carried out until a homogeneous blend is obtained.

If granules are to be used in the tabletting material, granules may beproduced in a manner known to a person skilled in the art, for exampleby dry granulation techniques in which the pharmaceutically active agentand/or delivery agents are compacted with the excipients to formrelatively large moldings, for example slugs or ribbons, which arecomminuted by grinding, and the ground material serves as the tablettingmaterial to be later compressed into tablets. Suitable equipment for drygranulation includes but is not limited to roller compaction equipmentfrom Gerteis, such as Gerteis MINI-PACTOR.

To compress the tabletting material into a solid oral dosage form, forexample a tablet, a tablet press may be used. In a tabletting press, thetabletting material is filled (e.g. force fed or gravity fed) into a diecavity. The tabletting material is then compressed by a punch withpressure. Subsequently, the resulting compact, or tablet is ejected fromthe tabletting press. The above mentioned compression process issubsequently referred to herein as the “compression process”. Suitabletablet presses include, but are not limited to, rotary tablet pressesand eccentric tablet presses. Examples of tablet presses include, butare not limited to, the Fette 102i (Fette GmbH), the Korsch XL100, theKorsch PH 106 rotary tablet press (Korsch AG, Germany), the Korsch EK-Oeccentric tabletting press (Korsch AG, Germany) and the Manesty F-Press(Manesty Machines Ltd., United Kingdom).

In some embodiments the method of preparation of the tablet comprises i)dry granulation of a mixture comprising the GLP-1 agonist (i.e. theGLP-1 peptide), filler and a binder; ii) dry granulation of a mixturecomprising the delivery agent, lubricant and/or filler iii) mixing ofthe granules with a lubricant, and then iv) compression of the blendinto tablets.

In some embodiments the invention relates to a process of producing apharmaceutical composition comprising granules comprising a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid and a lubricant, such amagnesium stearate, wherein said process comprises the steps: a) mixingsaid salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and saidlubricant for more than 5 minutes; and b) optionally roller compactingthe mixture of step a. In some embodiments the invention relates to aprocess of producing a pharmaceutical composition comprising a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid and a lubricant, such asmagnesium stearate, wherein said process comprises the steps: a) mixingsaid salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and saidlubricant for more than 5 minutes; and b) optionally roller compactingthe mixture of step a. In some embodiments the mixing in step a is atleast 6 minutes, such as at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45 or 50minutes. In some embodiments the mixing in step a is at least 10 minutesor at least 20 minutes. In some embodiments the mixing in step a is atleast 30 minutes or at least 40 minutes, such as at least 50 minutes. Insome embodiments the mixing in step a is in the range of from 6 minutesto 12 hours, such as from 10 minutes to 10 hours or from 15 minutes to 8hours. In some embodiments the duration of said mixing in step a is nomore than 12 hours, such as no more than 10, 8, 6, 4, or 2 hours. Insome embodiments the amount of lubricant is at least 0.25% (w/w) or atleast 0.5% (w/w), such as at least 1% (w/w) or at least 2% (w/w), ofsaid composition. In some embodiments the amount of lubricant is no morethan 10% (w/w), such as no more than 8, 7, or 6% (w/w), of saidcomposition.

In some embodiments the invention relates to a composition or a granuleobtained by the process as defined herein.

In some embodiments dry granulation is carried out by roller compaction.

In some embodiments the term “resistance to crushing of tablets” has themeaning defined in section 2.9.8 in the European Pharmacopoeia 7.5, 7thedition 2012; resistance to crushing may be measured inter alia inNewton (N) or kilopond (kP) using a jaw speed of 20 N/s (1 kP equals9.807 N).

In some embodiments the term “friability” has the meaning defined insection 2.9.7 in the European Pharmacopoeia 7.5, 7th edition 2012.

In some embodiments the term “particle size” means the volumedistribution of equivalent spherical diameters as determined by laserdiffraction at 3 bar dispersive pressure and at a obscuration in therange from 0.05-8% in a Malvern Mastersizer 2000 Scirocco 2000 (drymode) using general purpose enhanced sensitivity (Mie approximation) anda refractive index of 1.65.

In some embodiments the term “disintegration time” has the meaningdefined in section 2.9.1 in the European Pharmacopoeia 7.5, 7th edition2012 and the liquid medium used for the disintegration test is water-Ras defined in the European Pharmacopoeia 7.5, 7th edition 2012.

In some embodiments the term “compression force” means the force exertedbetween the upper and lower punches when compressing materials into atablet as determined by a load cell transducer that converts the forceinto electrical signal using a strain gauge; the compression force maybe measured inter alia in Newton (N) or kilopond (kP) (1 kP equals 9.807N).

In some embodiments the term “roller compaction force” means the forceexerted between the rolls of the roller compactor when compactingmaterials into a continuous strip of compressed material as determinedby a pressure transducer that converts the hydraulic pressure intoelectrical signal; the roller compaction force may be measured inkiloNewton (kN) or in kiloNewton per roll width (kN/cm).

Salt of N-(8-(2-hydroxybenzoyl)amino)caprylic Acid

The delivery agent used in the present invention is a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid. In some embodiments thedelivery agent is an absorption enhancer. The structural formula ofN-(8-(2-hydroxybenzoyl)amino)caprylate is shown in formula (I).

In some embodiments the salt of N-(8-(2-hydroxybenzoyl)amino)caprylicacid is in the caprylic acid form and/or the capraylate form. In someembodiments the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acidcomprises one monovalent cation, two monovalent cations or one divalentcation. In some embodiments the salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid is selected from the groupconsisting of the sodium salt, potassium salt and calcium salt of ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid.

Salts of N-(8-(2-hydroxybenzoyl)amino)caprylate may be prepared usingthe method described in e.g. WO96/030036, WO00/046182, WO01/092206 orWO2008/028859.

The salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid may becrystalline and/or amorphous. In some embodiments the delivery agentcomprises the anhydrate, monohydrate, dihydrate, trihydrate, a solvateor one third of a hydrate of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid as well as combinations thereof. In some embodiments thedelivery agent is a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acidas described in WO2007/121318. The salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid may be any polymorph thereof.

In some embodiments the delivery agent is sodiumN-(8-(2-hydroxybenzoyl)amino)caprylate (referred to as “SNAC” herein),also known as sodium 8-(salicyloylamino) octanoate.

In some embodiments the amount of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid in the composition is in the range of 0.6-3.5 mmol.In some embodiments the amount of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid in the composition is at least 0.6 mmol, such asselected from the group at least 0.8 mmol or at least 0.9 mmol. In someembodiments the amount of the salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid in the composition is up to2.5 mmol. In some embodiments the amount of the salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid in the composition is 0.6-2.0mmol. In some embodiments the amount of the salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid is 1 mmol, such as 1.08 mmol.

In some embodiments the amount of SNAC in the composition is in therange of 100-1000 mg. In some embodiments the amount of SNAC in thecomposition is at least 150 mg or at least 250 mg. In some embodimentsthe amount of SNAC in the composition is up to 800 mg, such as up to 700mg or up to 600 mg. In some embodiments the amount of SNAC in thecomposition is 300 mg.

In some embodiments the molar ratio between GLP-1 agonist (i.e. theGLP-1 peptide) and delivery agent in the composition is less than 10,such as less than 5 or less than 1. In some embodiments the molar ratiobetween GLP-1 agonist (i.e. the GLP-1 peptide) and delivery agent in thecomposition is less than 1/10, such as less than 1/100 or less than5/1000.

Pharmaceutically Active Agents

In some embodiments the composition of the invention comprises apharmaceutically active agent, such as a peptide or a protein. In someembodiments said pharmaceutically active agent is a GLP-1 peptide. Insome embodiments the GLP-1 peptide is referred to as a GLP-1 agonist.

The term “GLP-1 peptide” as used herein refers to a compound, whichfully or partially activates the human GLP-1 receptor. In someembodiments the “GLP-1 peptide” binds to a GLP-1 receptor, e.g., with anaffinity constant (K_(D)) or activate the receptor with a potency (EC₅₀)of below 1 μM, e.g. below 100 nM as measured by methods known in the art(see e.g. WO 98/08871) and exhibits insulinotropic activity, whereinsulinotropic activity may be measured in vivo or in vitro assays knownto those of ordinary skill in the art. For example, the GLP-1 peptidemay be administered to an animal with increased blood glucose (e.g.obtained using an Intravenous Glucose Tolerance Test (IVGTT), a personskilled in the art will be able to determine a suitable glucose dosageand a suitable blood sampling regime, e.g. depending on the species ofthe animal, for the IVGTT) and the plasma insulin concentration measuredover time.

In some embodiments the GLP-1 peptide is a GLP-1 analogue, optionallycomprising one substituent. The term “analogue” as used herein referringto a GLP-1 peptide (hereafter “peptide”) means a peptide wherein atleast one amino acid residue of the peptide has been substituted withanother amino acid residue and/or wherein at least one amino acidresidue has been deleted from the peptide and/or wherein at least oneamino acid residue has been added to the peptide and/or wherein at leastone amino acid residue of the peptide has been modified. Such additionor deletion of amino acid residues may take place at the N-terminal ofthe peptide and/or at the C-terminal of the peptide. In some embodimentsa simple nomenclature is used to describe the GLP-1 peptide, e.g.,[Aib8] GLP-1(7-37) designates an analogue of GLP-1(7-37) wherein thenaturally occurring Ala in position 8 has been substituted with Aib. Insome embodiments the GLP-1 peptide comprises a maximum of twelve, suchas a maximum of 10, 8 or 6, amino acids which have been alterered, e.g.,by substitution, deletion, insertion and/or modification, compared toe.g. GLP-1(7-37). In some embodiments the analogue comprises up to 10substitutions, deletions, additions and/or insertions, such as up to 9substitutions, deletions, additions and/or insertions, up to 8substitutions, deletions, additions and/or insertions, up to 7substitutions, deletions, additions and/or insertions, up to 6substitutions, deletions, additions and/or insertions, up to 5substitutions, deletions, additions and/or insertions, up to 4substitutions, deletions, additions and/or insertions or up to 3substitutions, deletions, additions and/or insertions, compared to e.g.GLP-1(7-37). Unless otherwise stated the GLP-1 comprises only L-aminoacids.

In some embodiments the term “GLP-1 analogue” or “analogue of GLP-1” asused herein refers to a peptide, or a compound, which is a variant ofthe human Glucagon-Like Peptide-1 (GLP-1 (7-37)). GLP-1 (7-37) has thesequence HAEGTFTSDV SSYLEGQAAKEFIAWLVKGRG (SEQ ID No: 1). In someembodiments the term “variant” refers to a compound which comprises oneor more amino acid substitutions, deletions, additions and/orinsertions.

In some embodiments the GLP-1 peptide exhibits at least 60%, 65%, 70%,80% or 90% sequence identity to GLP-1(7-37) over the entire length ofGLP-1(7-37). As an example of a method for determination of sequenceidentity between two analogues the two peptides [Aib8]GLP-1 (7-37) andGLP-1 (7-37) are aligned. The sequence identity of [Aib8]GLP-1 (7-37)relative to GLP-1(7-37) is given by the number of aligned identicalresidues minus the number of different residues divided by the totalnumber of residues in GLP-1(7-37). Accordingly, in said example thesequence identity is (31-1)/31.

In some embodiments the C-terminal of the GLP-1 peptide is an amide.

In some embodiments the GLP-1 peptide is GLP-1 (7-37) or GLP-1(7-36)amide. In some embodiments the GLP-1 peptide is exendin-4, thesequence of which is HGEGTFITSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS (SEQ IDNo: 2).

In some embodiments the GLP-1 peptide comprises one substituent which iscovalently attached to the peptide. In some embodiments the substituentcomprises a fatty acid or a fatty diacid. In some embodiments thesubstituent comprises a C16, C18 or C20 fatty acid. In some embodimentsthe substituent comprises a C16, C18 or C20 fatty diacid. In someembodiments the substituent comprises formula (X)

(X), wherein n is at least 13, such as n is 13, 14, 15, 16, 17, 18 or19. In some embodiments the substituent comprises formula (X), wherein nis in the range of 13 to 19, such as in the range of 13 to 17. In someembodiments the substituent comprises formula (X), wherein n is 13, 15or 17. In some embodiments the substituent comprises formula (X),wherein n is 13. In some embodiments the substituent comprises formula(X), wherein n is 15. In some embodiments the substituent comprisesformula (X), wherein n is 17. In some embodiments the substituentcomprises one or more 8-amino-3,6-dioxaoctanoic acid (OEG), such as twoOEG.

In some embodiments the substituent is[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl].

In some embodiments the substituent is[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl].

In some embodiments the GLP-1 peptide is semaglutide, also known asN-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37),which may be prepared as described in WO2006/097537, Example 4.

In some embodiments the composition comprises the GLP-1 peptide or apharmaceutically acceptable salt, amide, or ester thereof. In someembodiments the composition comprises the GLP-1 peptide one or morepharmaceutically acceptable counter ions.

In some embodiments the dosage of GLP-1 peptide is in the range of 0.01mg to 100 mg. In some embodiments the composition comprises an amount ofa GLP-1 peptide in the range of 1 to 80 mg or 5 to 60 mg. In someembodiments the composition comprises an amount of a GLP-1 peptide of 5mg, such as 10 mg or 60 mg.

In some embodiments the composition comprises an amount of a GLP-1peptide in the range of 0.05 to 25 μmol, such as in the range of 0.5 to20 μmol.

In some embodiments the GLP-1 peptide is selected from one or more ofthe GLP-1 peptides mentioned in WO93/19175, WO96/29342, WO98/08871,WO99/43707, WO99/43706, WO99/43341, WO99/43708, WO2005/027978,WO2005/058954, WO2005/058958, WO2006/005667, WO2006/037810,WO2006/037811, WO2006/097537, WO2006/097538, WO2008/023050,WO2009/030738, WO2009/030771 and WO2009/030774.

In some embodiments the GLP-1 peptide is selected from the groupconsisting ofN-epsilon37{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl[desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1 (7-37)amide;N-epsilon26{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl[desaminoHis7, Arg34]GLP-1-(7-37);N-epsilon37{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxy-nonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy] ethoxy}acetylamino)ethoxy]ethoxy}acetyl[Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-[2-(2-[2-(2-((R)-3-[1-(17-carboxyheptadecanoyl)piperidin-4-ylcarbonylamino]3-carboxypropionylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][,DesaminoHis7, Glu22 Arg26, Arg 34,Phe(m-CF3)28]GLP-1-(7-37)amide;N-epsilon26-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyryl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-{4-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]butyryl}[Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34, Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22, Arg26,Arg34, Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({4-[(trans-19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Arg26,Arg34,L ys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,A rg34, Lys37]GLP-1-(7-37);N-epsilon26[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino] ethoxy}ethoxy) acetylamino]ethoxy}ethoxy)acetyl[Aib8, Lys26]GLP-1 (7-37)amide; N-epsilon26[2-(2-[2-(2-[2-(2-((S)-2-[trans-4-((9-carboxynonadecanoylamino] methyl)cyclohexylcarbonylamino]-4-carboxybutanoylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8, Lys26] GLP-1 (7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexane-carbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Gu22,Arg26, Glu30,Arg34, Lys37]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{4-[4-(16-(1H-tetrazol-5-yl)-hexadecanoylsulfamoyl)butyrylamino]-butyrylamino}butyrylamino)butyrylamino] ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadeca noyl-sulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{4-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]butyrylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-34);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]-dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-34);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-34);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-36)amide;N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]dodecanoylamino}butyryl-amino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Lys33,Arg34]GLP-1-(7-34);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-36)amide;N-epsilon26-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino) butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Lys26,Arg34]GLP-1-(7-36)amide;N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino) butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34, Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxy-nonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy] ethoxy}acetyl[desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1 (7-37)amide;N-epsilon37{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino} propionylamino)ethoxy]ethoxy}acetylamino)ethoxy] ethoxy} acetyl [Aib8,Glu22,Arg26,Arg34, Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-[2-(2-[2-(2-((R)-3-[1-(17-carboxyhepta-decanoyl)piperidin-4-ylcarbonylamino]3-carboxy-propionylamino)ethoxy)ethoxy] acetylamino) ethoxy]ethoxy)acetyl] [DesaminoHis7,Glu22,Arg26, Arg34,Phe(m-CF3)28] GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl} amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexane-carbonyl}amino)butyrylamino]ethoxy}ethoxy) acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy} ethoxy)acetyl] [DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexane-carbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [DesaminoHis7,Glu22,Arg26,Glu30,Arg34,Lys37]GLP-1-(7-37);N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]dodecanoylamino} butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino) butyrylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-(3-((2-(2-(2-(2-(2-Hexadecyloxyethoxy)ethoxy)ethoxy) ethoxy)ethoxy)) propionyl)[DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)-amide;N-epsilon37-{2-(2-(2-(2-[2-(2-(4-(hexadecanoylamino)-4-carboxybutyryl-amino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}-[desaminoHis7,Glu22,Arg26,Glu30,Arg34,Lys37] GLP-1-(7-37)amide;N-epsilon37-{2-(2-(2-(2-[2-(2-(4-(hexadecanoylamino)-4-carboxy-butyryl-amino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy) acetyl)}-[desaminoHis7,Glu22, Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-(2-(2-(2-(2-(2-(2-(2-(2-(2-(octadecanoyl-amino)ethoxy)ethoxy)acetylamino)ethoxy) ethoxy)acetylamino) ethoxy)ethoxy)acetyl)[desaminoHis7,Glu22,Arg26,Arg34,Lys37] GLP-1 (7-37)amide;N-epsilon37-[4-(16-(1H-Tetrazol-5-yl)hexadecanoylsulfamoyl) butyryl][DesaminoHis7,Glu22,Arg26, Arg34, Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(19-carboxynonadecanoylamino)butyrylamino] ethoxy}ethoxy) acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26, Arg34,Lys37]GLP-1-(7-37);N-epsilon37-(2-{2-[2-((S)-4-carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyrylamino]butyrylamino}butyrylamino)ethoxy]ethoxy}acetyl)[DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon37-{2-[2-(2-{(S)-4-[(S)-4-(12-{4-[16-(2-tert-Butyl-2H-tetrazol-5-yl)-hexadecanoylsulfamoyl]butyrylamino}dodecanoylamino)-4-carboxybutyrylamino]-4-carboxybutyrylamino}ethoxy)ethoxy]acetyl}[DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1 (7-37);N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl][Aib8,Glu22, Arg26,Arg34,Lys37]GLP-1-(7-37);N-alpha37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl][Aib8,Glu22,Arg26,Arg34,epsilon-Lys37]GLP-1-(7-37)peptide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl][desaminoHis7, Glu22,Arg26,Arg34,Lys37] GLP-1-(7-37);N-epsilon36-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(15-carboxy-pentadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl][desaminoHis7, Glu22,Arg26,Glu30,Arg34,Lys36] GLP-1-(7-37)-Glu-Lyspeptide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyryl-amino]ethoxyethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl]-[Aib8,Glu22,Arg26,Arg34,Aib35,Lys37]GLP-1-(7-37);N-epsilon37-[(S)-4-carboxy-4-(2-{2-[2-(2-{2-[2-(17-carboxyheptadecanoylamino)ethoxy] ethoxy} acetylamino) ethoxy] ethoxy} acetylamino) butyryl][Aib8,Glu22,Arg26,34,Lys37] GLP-1 (7-37);N-epsilon37-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyryl-amino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][ImPr7,Glu22, Arg26,34,Lys37], GLP-1-(7-37);N-epsilon26-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy] acetylamino}ethoxy)ethoxy]acetyl},N-epsilon37-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxy-phenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl}-[Aib8,Arg34,Lys37]GLP-1 (7-37)-OH; N-epsilon26(17-carboxyhepta-decanoyl)-[Aib8,Arg34]GLP-1-(7-37)-peptide;N-epsilon26-(19-carboxynonadecanoyl)-[Aib8,Arg34]GLP-1-(7-37);N-epsilon26-(4-{[N-(2-carboxyethyl)-N-(15-carboxypenta-decanoyl)amino]methyl}benzoyl[Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino) ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(19-carboxynonadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][3-(4-Imidazolyl)Propionyl7,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-(carboxymethyl-amino)acetylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-3(S)-Sulfopropionylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37)-amide;N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34,Pro37]GLP-1-(7-37)amide; Aib8,Lys26(N-epsilon26-{2-(2-(2-(2-[2-(2-(4-(pentadecanoylamino)-4-carboxybutyrylamino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}), Arg34)GLP-1H(7-37)-OH;N-epsilon26-[2-(2-[2-(2-[2-(2-[4-{[N-(2-carboxyethyl)-N-(17-carboxyheptadecanoyl)amino]methyl}benzoyl)amino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37);N-alpha7-formyl,N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoyl-amino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Arg34]GLP-1-(7-37);N-epsilon2626-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Glu22, Arg34] GLP-1-(7-37);N-epsilon26{3-[2-(2-{2-[2-(2-{2-[2-(2-[4-(15-(N—((S)-1,3-dicarboxypropyl)carbamoyl) pentadecanoylamino)-(S)-4-carboxybutyrylamino]ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]propionyl}[Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-{[N-(2-carboxyethyl)-N-(17-carboxy-heptadecanoyl)amino]methyl}benzoyl)amino](4(S)-carboxybutyryl-amino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34] GLP-1(7-37);N-epsilon26-{(S)-4-carboxy-4-((S)-4-carboxy-4-((S)-4-carboxy-4-((S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyrylamino)butyrylamino)butyrylamino)butyrylamino}[Aib8,Arg34]GLP-1-(7-37);N-epsilon26-4-(17-carboxyheptadecanoyl-amino)-4(S)-carboxybutyryl-[Aib8,Arg34]GLP-1-(7-37);N-epsilon26-{3-[2-(2-{2-[2-(2-{2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]propionyl}[Aib8,Arg34]GLP-1-(7-37);N-epsilon26-{2-(2-(2-(2-[2-(2-(4-(17-carboxyheptadecanoylamino)-4-carboxybutyrylamino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}-[Aib8,22,27,30,35,Arg34,Pro37,Lys26] GLP-1 (7-37)amide;N-epsilon26-[2-(2-[2-[4-(21-carboxyuneicosanoylamino)-4(S)-carboxybutyrylamino]ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);andN-epsilon26-[2-(2-[2-(2-[2-(2-[4-(21-carboxyuneicosanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37).

In one embodiment GLP-1 peptides can be produced by appropriatederivatisation of an appropriate peptide backbone which has beenproduced by recombinant DNA technology or by peptide synthesis (e.g.,Merrifield-type solid phase synthesis) as known in the art of peptidesynthesis and peptide chemistry.

In one embodiment the production of peptides like GLP-1(7-37) and GLP-1analogues is well known in the art. The GLP-1 moiety of the GLP-1peptide of the invention (or fragments thereof) may for instance beproduced by classical peptide synthesis, e.g., solid phase peptidesynthesis using t-Boc or Fmoc chemistry or other well establishedtechniques, see, e.g., Greene and Wuts, “Protective Groups in OrganicSynthesis”, John Wiley & Sons, 1999, Florencio Zaragoza Dorwald,“Organic Synthesis on solid Phase”, Wiley-VCH Verlag GmbH, 2000, and“Fmoc Solid Phase Peptide Synthesis”, Edited by W. C. Chan and P. D.White, Oxford University Press, 2000.

In one embodiment GLP-1 peptides may be produced by recombinant methods,viz. by culturing a host cell containing a DNA sequence encoding theGLP-1 peptide and capable of expressing the peptide in a suitablenutrient medium under conditions permitting the expression of thepeptide. Non-limiting examples of host cells suitable for expression ofthese peptides are: Escherichia coli, Saccharomyces cerevisiae, as wellas mammalian BHK or CHO cell lines.

In one embodiment GLP-1 peptides of the invention which includenon-natural amino acids and/or a covalently attached N-terminal mono- ordipeptide mimetic may e.g. be produced as described in the experimentalpart. Or see e.g., Hodgson et al: “The synthesis of peptides andproteins containing non-natural amino acids”, Chemical Society Reviews,vol. 33, no. 7 (2004), p. 422-430; and WO 2009/083549 A1 entitled“Semi-recombinant preparation of GLP-1 analogues”.

Pharmaceutical Indications

The present invention also relates to a composition of the invention foruse as a medicament.

In particular embodiments, the composition of the invention may be usedfor the following medical treatments, all preferably relating one way orthe other to diabetes:

(i) prevention and/or treatment of all forms of diabetes, such ashyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1diabetes, non-insulin dependent diabetes, MODY (maturity onset diabetesof the young), gestational diabetes, and/or for reduction of HbA1C;

(ii) delaying or preventing diabetic disease progression, such asprogression in type 2 diabetes, delaying the progression of impairedglucose tolerance (IGT) to insulin requiring type 2 diabetes, and/ordelaying the progression of non-insulin requiring type 2 diabetes toinsulin requiring type 2 diabetes;

(iii) improving β-cell function, such as decreasing β-cell apoptosis,increasing β-cell function and/or β-cell mass, and/or for restoringglucose sensitivity to β-cells; (iv) prevention and/or treatment ofcognitive disorders;

(v) prevention and/or treatment of eating disorders, such as obesity,e.g. by decreasing food intake, reducing body weight, suppressingappetite, inducing satiety; treating or preventing binge eatingdisorder, bulimia nervosa, and/or obesity induced by administration ofan antipsychotic or a steroid; reduction of gastric motility; and/ordelaying gastric emptying;

(vi) prevention and/or treatment of diabetic complications, such asneuropathy, including peripheral neuropathy; nephropathy; orretinopathy;

(vii) improving lipid parameters, such as prevention and/or treatment ofdyslipidemia, lowering total serum lipids; lowering HDL; lowering small,dense LDL; lowering VLDL: lowering triglycerides; lowering cholesterol;increasing HDL; lowering plasma levels of lipoprotein a (Lp(a)) in ahuman; inhibiting generation of apolipoprotein a (apo(a)) in vitroand/or in vivo;

(iix) prevention and/or treatment of cardiovascular diseases, such assyndrome X; atherosclerosis; myocardial infarction; coronary heartdisease; stroke, cerebral ischemia; an early cardiac or earlycardiovascular disease, such as left ventricular hypertrophy; coronaryartery disease; essential hypertension; acute hypertensive emergency;cardiomyopathy; heart insufficiency; exercise tolerance; chronic heartfailure; arrhythmia; cardiac dysrhythmia; syncopy; atheroschlerosis;mild chronic heart failure; angina pectoris; cardiac bypass reocclusion;intermittent claudication (atheroschlerosis oblitterens); diastolicdysfunction; and/or systolic dysfunction;

(ix) prevention and/or treatment of gastrointestinal diseases, such asinflammatory bowel syndrome; small bowel syndrome, or Crohn's disease;dyspepsia; and/or gastric ulcers;

(x) prevention and/or treatment of critical illness, such as treatmentof a critically ill patient, a critical illness poly-nephropathy (CIPNP)patient, and/or a potential CIPNP patient; prevention of criticalillness or development of CIPNP; prevention, treatment and/or cure ofsystemic inflammatory response syndrome (SIRS) in a patient; and/or forthe prevention or reduction of the likelihood of a patient sufferingfrom bacteraemia, septicaemia, and/or septic shock duringhospitalisation; and/or

(xi) prevention and/or treatment of polycystic ovary syndrome (PCOS).

In a particular embodiment, the indication is selected from the groupconsisting of (i)-(iii) and (v)-(iix), such as indications (i), (ii),and/or (iii); or indication (v), indication (vi), indication (vii),and/or indication (iix).

In another particular embodiment, the indication is (i). In a furtherparticular embodiment the indication is (v). In a still furtherparticular embodiment the indication is (iix).

The following indications are particularly preferred: Type 2 diabetes,and/or obesity.

Particular Embodiments

1. A granule comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylicacid and a lubricant, wherein the granule is obtained by mixing saidsalt of N-(8-(2-hydroxybenzoyl)amino)caprylic and said lubricant formore than 5 minutes, such as at least 10, 15, 20, 25, 30, 35, 40, 45 or50 minutes.2. A granule according to embodiment 1, wherein the duration of saidmixing is at least 6 minutes, such as at least 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35,40, 45 or 50 minutes, such as at least 10, 20, 30, 40 or 50 minutes.3. A granule according to any one of the preceding embodiments, whereinthe amount of said lubricant is at least 0.25% (w/w) or at least 0.5%(w/w), such as at least 1% (w/w) or at least 2% (w/w), of said granule.4. A granule according to any one of the preceding embodiments, whereinthe amount of said lubricant is no more than 10% (w/w), such as no morethan 8, 7, or 6% (w/w), of said granule.5. A granule according to any one of the preceding embodiments, whereinsaid salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is SNAC.6. A granule according to any one of the preceding embodiments, whereinsaid lubricant is magnesium stearate.7. A granule according to any one of the preceding embodiments, whereinsaid granule comprises granules which have been manufactured by drygranulation, such as roller compaction.8. A granule according to any one of the preceding embodiments, whereinthe duration of said mixing is at least 10, 20, 30, 40 or 50 minutes,such as at least 30 minutes or at least 40 minutes, such as at least 50minutes.9. A granule according to any one of the preceding embodiments, whereinthe duration of said mixing is no more than 12 hours, such as no morethan 10, 8, 6, 4, or 2 hours.10. A composition comprising said granule as defined in any one of thepreceding embodiments,11. A pharmaceutical composition according to any one of the precedingembodiments, wherein said composition further comprises apharmaceutically active ingredient.12. A pharmaceutical composition according to any one of the precedingembodiments, wherein said composition further comprises a GLP-1 peptide.13. A pharmaceutical composition according to embodiment 4, wherein saidGLP-1 peptide comprises an albumin binding moiety.14. A pharmaceutical composition according to embodiment 4, wherein saidGLP-1 peptide isN-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37).15. A composition according to any one of the preceding embodiments,wherein said composition further comprises one or more pharmaceuticallyacceptable excipients.16. A composition according to any one of the preceding embodiments,wherein said composition further comprises one or more ingredientsselected from the group consisting of a filler, such as microcrystallinecellulose, and a binder, such as povidone.17. A composition according to any one of the preceding embodiments,wherein said further comprises extragranular lubricant, such asmagnesium stearate.18. A composition according to any one of the preceding embodiments,wherein said composition comprises granules which have been manufacturedby dry granulation.19. A composition according to embodiment 13, wherein said compositioncomprises granules which have been manufactured by roller compaction.20. A composition according to any one of the preceding embodiments,wherein said composition is in the form of a solid dosage form.21. A composition according to embodiment 20, wherein said solid dosageform is a tablet.22. A composition according to embodiment 20, wherein said compositionis in the form of a capsule.23. A composition according to embodiment 20, wherein said compositionis in the form of a sachet.24. A process of producing a pharmaceutical composition comprisinggranules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acidand a lubricant, such a magnesium stearate, wherein said processcomprises the steps:a) mixing said salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid andsaid lubricant for more than 5 minutes; andb) optionally roller compacting the mixture of step a.25. A process according to embodiment 24, wherein the duration of saidmixing in step a is at least 6 minutes, such as at least 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30, 35, 40, 45 or 50 minutes.26. A process according to embodiment 24 or 25, wherein the duration ofsaid mixing in step a is at least 20 minutes, such as at least 30minutes, at least 40 minutes or at least 50 minutes.27. A process according to any one of embodiments 24-26, wherein theamount of said lubricant is at least 0.25% (w/w) or at least 0.5% (w/w),such as at least 1% (w/w) or at least 2% (w/w), of said composition.28. A process according to any one of embodiments 24-27, wherein theduration of said mixing in step a is at least at least 10, 20, 30, 40 or50 minutes, such as 30 minutes or at least 40 minutes, such as at least50 minutes.29. A process according to any one of embodiments 24-28, wherein theamount of said lubricant is at least 1% (w/w), such as at least 2%(w/w), of said composition.30. A process according to any one of embodiments 24-29, wherein,wherein the amount of said lubricant is no more than 10% (w/w), such asno more than 8, 7, or 6% (w/w), of said composition.31. A process according to any one of embodiments 24-30, wherein saidlubricant is magnesium stearate.32. A process according to any one of embodiments 24-31, wherein saidsalt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is SNAC.33. A process according to any one of embodiments 24-32, wherein saidcomposition further comprises one or more pharmaceutically acceptableexcipients.34. A process according to any one of embodiments 24-33, wherein saidcomposition further comprises a filler, such as microcrystallinecellulose.35. A process according to any one of embodiments 24-34, wherein saidcomposition further comprises a binder, such as povidone.36. A process according to any one of embodiments 24-35, wherein saidcomposition is in the form of a solid dosage form.37. A process composition according to embodiment 36, wherein saidcomposition is a tablet.38. A process composition according to embodiment 36, wherein saidcomposition is in the form of a capsule.39. A process composition according to embodiment 36, wherein saidcomposition is in the form of a sachet.40. A process according to any one of embodiments 24-39, wherein theduration of said mixing in step a is no more than 12 hours, such as nomore than 10, 8, 6, 4, or 2 hours.41. A granule obtained by the process as defined in any one ofembodiments 24-40.42. A pharmaceutical composition obtained by the process as defined inany one of embodiments 24-40.43. A granule as defined in any one of embodiments 1-9 or 41 or acomposition as defined in any one of embodiments 10-23 or 42 for use inmedicine.44. A granule as defined in any one of embodiments 1-9 or 41 or acomposition as defined in any one of embodiments 10-23 or 42 fortreatment of diabetes or obesity.45. A granule or a composition according to embodiment 43 or 44, whereinsaid composition or said granule is administered orally.46. A method for treatment of diabetes or obesity comprisingadministering a granule as defined in any one of embodiments 1-9 or 41or a composition as defined in any one of embodiments 10-23 or 42 to apatient in need thereof.47. A method according to embodiment 46, wherein said composition orsaid granule is administered orally.48. A granule as defined in any one of embodiments 1-9 or 41 or acomposition as defined in any one of embodiments 10-23 or 42 for use inmedicine, such as for treatment of diabetes or obesity, wherein saidcomposition or said granule is optionally administered orally.

Further Particular Embodiments

The following are further particular embodiments of the invention:

1. A pharmaceutical composition comprising a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid and a lubricant, wherein thecomposition is obtained by mixing said salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic and said lubricant for more than 5minutes.

2. A composition according to embodiment 1, wherein the duration of saidmixing is at least 6 minutes, such as at least 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35,40, 45 or 50 minutes, such as at least 10, 20, 30, 40 or 50 minutes.3. A composition according to embodiment 1 or 2, wherein the amount ofsaid lubricant is at least 0.25% (w/w) or at least 0.5% (w/w), such asat least 1% (w/w) or at least 2% (w/w), of said composition.4. A composition according to any one of the preceding embodiments,wherein the amount of said lubricant is no more than 10% (w/w), such asno more than 8, 7, or 6% (w/w), of said composition.5. A composition according to any one of the preceding embodiments,wherein said salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is SNAC.6. A composition according to any one of the preceding embodiments,wherein said composition further comprises a pharmaceutically activeingredient.7. A composition according to any one of the preceding embodiments,wherein said composition further comprises a GLP-1 peptide.8. A according to embodiment 7, wherein said GLP-1 peptide comprises analbumin binding moiety.9. A composition according to embodiment 7 or 8, wherein said GLP-1peptide isN-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37).10. A composition according to any one of the preceding embodiments,wherein said lubricant is magnesium stearate.11. A composition according to any one of the preceding embodiments,wherein said composition further comprises one or more ingredientsselected from the group consisting of a filler, such as microcrystallinecellulose, and a binder, such as povidone.12. A composition according to any one of the preceding embodiments,wherein said composition further comprises one or more pharmaceuticallyacceptable excipients.13. A composition according to any one of the preceding embodiments,wherein said composition comprises granules which have been manufacturedby dry granulation.14. A composition according to embodiment 13, wherein said compositioncomprises granules which have been manufactured by roller compaction.15. A composition according to any one of the preceding embodiments,wherein said composition is in the form of a solid dosage form.16. A composition according to embodiment 15, wherein said solid dosageform is a tablet.17. A composition according to embodiment 15, wherein said compositionis in the form of a capsule.18. A composition according to embodiment 15, wherein said compositionis in the form of a sachet.19. A composition according to any one of embodiments 1-18, wherein theduration of said mixing is at least 10, 20, 30, 40 or 50 minutes, suchas at least 30 minutes or at least 40 minutes, such as at least 50minutes.20. A composition according to any one of embodiments 1-19, wherein theduration of said mixing is no more than 12 hours, such as no more than10, 8, 6, 4, or 2 hours.21. A process of producing a pharmaceutical composition comprising asalt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a lubricant, sucha magnesium stearate, wherein said process comprises the steps:

-   -   a. mixing said salt of N-(8-(2-hydroxybenzoyl)amino)caprylic        acid and said lubricant for more than 5 minutes; and    -   b. optionally roller compacting the mixture of step a.        22. A process according to embodiment 21, wherein the duration        of said mixing in step a is at least 6 minutes, such as at least        7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,        24, 25, 26, 27, 28, 29, 30, 35, 40, 45 or 50 minutes.        23. A process according to embodiment 21 or 22, wherein the        duration of said mixing in step a is at least at least 10, 20,        30, 40 or 50 minutes, such as 30 minutes or at least 40 minutes,        such as at least 50 minutes.        24. A process according to any one of embodiments 21-23, wherein        the amount of said lubricant is at least 1% (w/w), such as at        least 2% (w/w), of said composition.        25. A process according to any one of embodiments 21-24,        wherein, wherein the amount of said lubricant is no more than        10% (w/w), such as no more than 8, 7, or 6% (w/w), of said        composition.        26. A process according to any one of embodiments 21-25, wherein        said lubricant is magnesium stearate.        27. A process according to any one of embodiments 21-26, wherein        said salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is SNAC.        28. A process according to any one of embodiments 21-27, wherein        said composition further comprises one or more pharmaceutically        acceptable excipients.        29. A process according to any one of embodiments 21-28, wherein        said composition further comprises a filler, such as        microcrystalline cellulose.        30. A process according to any one of embodiments 21-29, wherein        said composition further comprises a binder, such as povidone.        31. A process according to any one of embodiments 21-30, wherein        said composition is in the form of a solid dosage form.        32. A process composition according to embodiment 31, wherein        said composition is a tablet.        33. A process composition according to embodiment 31, wherein        said composition is in the form of a capsule.        34. A process composition according to embodiment 31, wherein        said composition is in the form of a sachet.        35. A process according to any one of embodiments 21-34, wherein        the duration of said mixing in step a is no more than 12 hours,        such as no more than 10, 8, 6, 4, or 2 hours.        36. A composition obtained by the process as defined in any one        of embodiments 21-35.        37. A granule obtained by the process as defined in any one of        embodiments 21-35.        38. A composition as defined in any one of embodiments 1-20 or        36 or a granule as defined in embodiment 37 for use in medicine.        39. A composition as defined in any one of embodiments 1-20 or        36 or a granule as defined in embodiment 37 for treatment of        diabetes or obesity.        40. A composition according to embodiment 38 or 39, wherein said        composition or said granule is administered orally.        41. A method for treatment of diabetes or obesity comprising        administering the composition as defined in any one of        embodiments 1-20 or 36 or a granule as defined in embodiment 37        to a patient in need thereof.        42. A method according to embodiment 41, wherein said        composition or said granule is administered orally.

EXAMPLES

Materials and Methods

General Methods of Preparation

Dry Granulation

Dry granulation was carried out by roller compaction on a GerteisMINI-PACTOR using smooth rolls, a 0.63 mm wire mesh screen, and agranulator speed of 60 rpm. The roll speed was set at 1.5 or 3.0 rpm androller compaction forces around 1 to 13 kN/cm were applied at a gap of1.0 mm. Subsequent to dry granulation comminution of the moldings intogranules was carried out.

Tablet Preparation

Tablets were produced on a Korsch PH106 or a Fette 102i mounted with agravity feeder and one or four punches, respectively, resulting in 13mm×7.5 mm convex oval tablets having no score. For the Korsch PH106 thepress speed was set around 25 rpm and the counter pressure was adjustedto 40 kN. For the Fette 102i the press speed was set at 20 rpm. The fillvolume was adjusted to obtain tablets having target weights from 404 to414 mg and compression forces around 2 to 17 kN were applied.

General Methods of Detection and Characterisation

Resistance to Crushing of Tablets

Resistance to crushing of tablets was determined according to section2.9.8 in the European Pharmacopoeia 7.5, 7th edition 2012 and at a jawspeed of 20 N/s.

Friability

Friability was determined according to section 2.9.7 in the EuropeanPharmacopoeia 7.5, 7th edition 2012.

Particle Size

Particle size, i.e. the volume distribution of equivalent sphericaldiameters, was determined by laser diffraction at 3 bar dispersivepressure and at a obscuration in the range from 0.05-8% in a MalvernMastersizer 2000 Scirocco 2000 (dry mode) using general purpose enhancedsensitivity (Mie approximation) and a refractive index of 1.65.

Disintegration Time

Disintegration time was determined according to section 2.9.1 in theEuropean Pharmacopoeia 7.5, 7th edition 2012 and the liquid medium usedfor the disintegration test was water-R as defined in the EuropeanPharmacopoeia 7.5, 7th edition 2012.

Compression Force

Compression force, i.e. the force exerted between the upper and lowerpunch when compressing materials into a tablet, was determined by a loadcell transducer that converted the force into electrical signal using astrain gauge.

Roller Compaction Force

Roller compaction force, i.e. the force exerted between the rolls of theroller compactor when compacting materials into a continuous strip ofcompressed material, was determined by a pressure transducer thatconverts the hydraulic pressure into electrical signal; the rollercompaction force may be measured in kiloNewton (kN) or in kiloNewton perroll width (kN/cm).

Example 1: Preparation and Characterisation of Compositions ComprisingDifferent Amounts of Lubricant

Three granule compositions each containing 2, 2.5, or 5% (w/w) ofmagnesium stearate, respectively, were manufactured for three differenttablet compositions; their compositions are described in Table 1.

TABLE 1 Composition of tablets Granule Fraction/ Composition typeComponent Extragranular A B C SNAC First granule 300 mg/tablet 300mg/tablet 300 mg/tablet fraction Magnesium stearate First granule 2%(w/w) 2.5% (w/w) 5% (w/w) fraction 6 mg/tablet 8 mg/tablet 16 mg/tabletMicrocrystalline Second granule 90 mg/tablet 90 mg/tablet 90 mg/tabletcellulose fraction (Avicel PH 101) Povidone K 90 Extragranular 8mg/tablet 8 mg/tablet 8 mg/tablet (Kollidon 90F) Tablet weight 404 mg406 mg 414 mg

The tablet compositions were prepared by mixing the delivery agent SNACand magnesium stearate at 25 rpm prior to dry granulation; the mixingtime of enhancer and lubricant prior to granulation for each experimentis shown in Table 2.

TABLE 2 Preparation of tablets Exp. 1 Exp. 2 Exp. 3 Exp. 4 Exp. 5Composition type A C A C B Amount of magnesium 2.0 5.0 2.0 5.0 2.5stearate (% (w/w)) Mixing time of first 40 40 4 4 20 granule fraction(i.e. delivery agent and lubricant) (min)

Dry granulation was carried out as described in the section GeneralMethods of Preparation. Particles <180 μm were removed from both granulefractions prior to weighing and blending for the tabletting process. Theblending prior to the tabletting process was performed for 5 min at 32rpm. Tabletting was carried out as described in the section GeneralMethods of Preparation.

The particle size of the first granule fraction in the tabletcompositions were characterised by laser diffraction as described in thesection General Methods of Detection and Characterisation. The resultsare shown in Table 3.

TABLE 3 Particle sizes of granules determined by laser diffraction.Volume %(v/v) Size (μm) Exp. 1 Exp. 2 Exp. 3 Exp. 4 Exp. 5 0.011 0.000.00 0.00 0.00 0.00 0.013 0.00 0.00 0.00 0.00 0.00 0.015 0.00 0.00 0.000.00 0.00 0.017 0.00 0.00 0.00 0.00 0.00 0.020 0.00 0.00 0.00 0.00 0.000.023 0.00 0.00 0.00 0.00 0.00 0.026 0.00 0.00 0.00 0.00 0.00 0.030 0.000.00 0.00 0.00 0.00 0.035 0.00 0.00 0.00 0.00 0.00 0.040 0.00 0.00 0.000.00 0.00 0.046 0.00 0.00 0.00 0.00 0.00 0.052 0.00 0.00 0.00 0.00 0.000.060 0.00 0.00 0.00 0.00 0.00 0.069 0.00 0.00 0.00 0.00 0.00 0.079 0.000.00 0.00 0.00 0.00 0.091 0.00 0.00 0.00 0.00 0.00 0.105 0.00 0.00 0.000.00 0.00 0.120 0.00 0.00 0.00 0.00 0.00 0.138 0.00 0.00 0.00 0.00 0.000.158 0.00 0.00 0.00 0.00 0.00 0.182 0.00 0.00 0.00 0.00 0.00 0.209 0.000.00 0.00 0.00 0.00 0.240 0.00 0.00 0.00 0.00 0.00 0.275 0.00 0.00 0.000.00 0.00 0.316 0.00 0.00 0.00 0.00 0.00 0.363 0.00 0.00 0.00 0.00 0.000.417 0.00 0.00 0.00 0.00 0.00 0.479 0.00 0.00 0.00 0.00 0.00 0.550 0.000.00 0.00 0.00 0.00 0.631 0.00 0.00 0.02 0.00 0.00 0.724 0.05 0.05 0.100.05 0.04 0.832 0.13 0.12 0.17 0.12 0.10 0.955 0.23 0.22 0.29 0.22 0.191.096 0.35 0.32 0.41 0.32 0.28 1.259 0.49 0.45 0.56 0.45 0.40 1.445 0.660.59 0.75 0.60 0.54 1.660 0.86 0.74 0.97 0.76 0.70 1.905 1.10 0.91 1.230.94 0.87 2.188 1.35 1.09 1.52 1.13 1.05 2.512 1.62 1.27 1.83 1.32 1.232.884 1.90 1.44 2.16 1.50 1.40 3.311 2.16 1.59 2.47 1.67 1.55 3.802 2.401.71 2.74 1.80 1.68 4.365 2.58 1.79 2.96 1.90 1.77 5.012 2.70 1.84 3.101.95 1.81 5.754 2.73 1.83 3.13 1.95 1.80 6.607 2.68 1.77 3.05 1.89 1.747.586 2.53 1.66 2.87 1.77 1.63 8.710 2.30 1.51 2.59 1.62 1.47 10.0002.00 1.34 2.24 1.43 1.29 11.482 1.67 1.16 1.85 1.23 1.09 13.183 1.340.98 1.46 1.03 0.90 15.136 1.03 0.82 1.10 0.86 0.73 17.378 0.78 0.700.80 0.72 0.59 19.953 0.59 0.63 0.58 0.62 0.51 22.909 0.48 0.60 0.440.57 0.47 26.303 0.44 0.62 0.38 0.57 0.48 30.200 0.46 0.67 0.38 0.600.52 34.674 0.52 0.74 0.41 0.67 0.59 39.811 0.60 0.82 0.47 0.75 0.6845.709 0.70 0.92 0.55 0.85 0.78 52.481 0.80 1.03 0.65 0.97 0.89 60.2560.92 1.15 0.75 1.10 1.03 69.183 1.06 1.30 0.88 1.26 1.18 79.433 1.221.48 1.03 1.44 1.36 91.201 1.40 1.69 1.21 1.64 1.56 104.713 1.61 1.931.41 1.87 1.80 120.226 1.86 2.20 1.64 2.12 2.07 138.038 2.13 2.51 1.892.40 2.37 158.489 2.45 2.86 2.17 2.71 2.73 181.970 2.80 3.25 2.46 3.053.14 208.930 3.19 3.69 2.79 3.44 3.62 239.883 3.59 4.16 3.12 3.86 4.15275.423 4.01 4.65 3.46 4.32 4.71 316.228 4.39 5.10 3.79 4.75 5.24363.078 4.69 5.45 4.06 5.12 5.67 416.869 4.85 5.62 4.24 5.34 5.91478.630 4.81 5.52 4.28 5.34 5.87 549.541 4.51 5.10 4.13 5.05 5.48630.957 3.94 4.34 3.77 4.46 4.74 724.436 3.10 3.27 3.20 3.59 3.70831.764 2.14 2.07 2.49 2.53 2.50 954.993 0.98 0.73 1.71 1.40 1.241096.478 0.12 0.00 0.94 0.38 0.17 1258.925 0.00 0.00 0.26 0.00 0.001445.440 0.00 0.00 0.05 0.00 0.00 1659.570 0.00 0.00 0.00 0.00 0.001905.461 0.00 0.00 0.00 0.00 0.00 2187.762 0.00 0.00 0.00 0.00 0.002511.886 0.00 0.00 0.00 0.00 0.00 2884.032 0.00 0.00 0.00 0.00 0.003311.311 0.00 0.00 0.00 0.00 0.00 3801.894 0.00 0.00 0.00 0.00 0.004365.158 0.00 0.00 0.00 0.00 0.00 5011.872 0.00 0.00 0.00 0.00 0.005754.399 0.00 0.00 0.00 0.00 0.00 6606.934 0.00 0.00 0.00 0.00 0.007585.776 0.00 0.00 0.00 0.00 0.00 8709.636 0.00 0.00 0.00 0.00 0.0010000.000 0.00 0.00 0.00 0.00 0.00

Resistance to crushing and compression force of the tablets weredetermined as described in the section General Methods of Detection andCharacterisation. The results are shown in Table 4.

TABLE 4 Tablet resistance to crushing as a function of the compressionforce for the experiments. Exp. 1 Exp. 2 Exp. 3 Exp. 4 Exp. 5 CF¹ TRC²CF TRC CF TRC CF TRC CF TRC (kN) (N) (kN) (N) (kN) (N) (kN) (N) (kN) (N)3.4 48.6 2.3 25.4 3.4 53.1 2.3 24.5 2.6 31.1 4.8 85.4 3.6 47.2 5.5 94.63.5 43.3 3.6 49.8 8.2 139.0 5.9 81.8 8.5 142.7 5.9 78.5 5.7 87.2 11.3180.6 9.2 122.6 9.6 164.1 9.6 123.6 7.7 116.9 14.8 208.8 14.3 153.6 12.4185.6 13.9 148.3 10.5 160.2 17.1 226.8 16.6 168.3 15.1 210.6 16.6 161.212.6 180.9 — — — — — — — — 15.3 189.4 — — — — — — — — 17.0 195.3 ¹CF:Compression force. ²TRC: Tablet resistance to crushing.

Disintegration time and compression force of the tablets were determinedas described in the section General Methods of Detection andCharacterisation. The results are shown in Table 5.

TABLE 5 Tablet disintegration time as a function of the compressionforce for the experiments. Exp. 1 Exp. 2 Exp. 3 Exp. 4 Exp. 5 CF¹ TDT²CF TDT CF TDT CF TDT CF TDT (kN) (min) (kN) (min) (kN) (min) (kN) (min)(kN) (mm) 3.4 4.8 2.3 5.1 3.4 5.7 2.3 3.9 2.6 3.5 4.8 6.7 3.6 7.4 5.57.2 3.5 5.9 3.6 5.1 8.2 8.1 5.9 9.4 8.5 8.1 5.9 7.9 5.7 6.6 11.3 7.8 9.29.2 9.6 7.4 9.6 8.7 7.7 7.4 14.8 8.1 14.3 10.2 12.4 8.8 13.9 10.2 10.58.6 17.1 8.7 16.6 10.8 15.1 8.0 16.6 11.4 12.6 8.7 — — — — — — — — 15.38.8 — — — — — — — — 17.0 8.0 ¹CF: Compression force. ²TDT: Tabletdisintegration time.

Friability of the tablets was determined as described in the sectionGeneral Methods of Detection and Characterisation. The friability of thetablets from experiment 1-5 was found to be <0.2% (w/w).

These results show that for each of the three compositions A, B and C,the time used to mix the blend of magnesium stearate and SNAC (4, 20, or40 minutes) prior to granulation did not influence the size of thegranules (see Table 3) whereas the extent of granulation was increasedwith increasing mixing time. In addition, the crushing strength (seeTable 4), the disintegration time (see Table 5) and the friability(<0.2% (w/w)) of the tablets from experiment 1-5 were not influenced bythe mixing time used to mix magnesium stearate and SNAC prior togranulation.

Example 2: Preparation and Characterisation of Compositions PreparedUsing Different Granulation Methods

Tablet compositions containing the components shown in Table 6 wereprepared using different methods of preparation.

TABLE 6 Composition of tablets Granule Fraction/ Extra- CompositionComposition Components granular Type D Type E SNAC First 300 mg/tablet300 mg/tablet Magnesium stearate granule 7.7 mg/tablet 7.7 mg/tabletMicrocrystalline fraction None 57 mg/tablet cellulose (Avicel PH 101)Microcrystalline Second 90 mg/tablet 33 mg/tablet cellulose granule(Avicel PH 101) fraction Povidone K 90 8 mg/tablet 8 mg/tablet (Kollidon90F) Magnesium stearate Extra- 2 mg/tablet 2 mg/tablet granular Tabletweight 407.7 mg 407.7 mg

Tablets with Composition Type E were made by preparing two granulefractions by dry granulation; the first granule fraction contained thedelivery agent SNAC, microcrystalline cellulose and 2.1% magnesiumstearate and the second granule fraction contained microcrystallinecellulose and povidone. A two-step mixing procedure was performed forthe first granule fraction, i.e. containing SNAC, prior to the drygranulation process: In the first mixing step SNAC and magnesiumstearate was mixed for 50 minutes at 25 rpm and in the second mixingstep microcrystalline cellulose was added to the SNAC/magnesium stearateblend and mixed for another 5, 20, or 25 min at 25 rpm; thus, thelubrication process was performed for a total of 55, 70, or 75 minutes,respectively, at 25 rpm prior to dry granulation. For the second granulefraction, i.e. containing microcrystalline cellulose and povidone themixing was performed for 40 min at 25 rpm, prior to dry granulation. Drygranulation was carried out as described in the section General Methodsof Preparation. Particles <90 μm were removed from the first granulefraction prior to weighing and blending with the second granule fractionand extragranular magnesium stearate. The two granule fractions weremixed for 10 min at 25 rpm before extragranular magnesium stearate wasmixed with the two granule fractions for additional 2 minutes at 25 rpmprior to the tabletting process. Tablets were prepared as described inthe section General Methods of Preparation.

Tablets with Composition Type D were made by preparing two granulefractions by dry granulation; the first granule fraction contained thedelivery agent SNAC and 2.5% magnesium stearate and the second granulefraction contained microcrystalline cellulose and povidone. SNAC andmagnesium stearate were mixed for 20, 50, or 75 min, respectively, at 25rpm prior to dry granulation. For the second granule fraction, i.e.containing microcrystalline cellulose and povidone, the mixing wasperformed for 20 min at 25 rpm, prior to dry granulation. Drygranulation was carried out as described in the section General Methodsof Preparation. Particles <90 μm were removed from the first granulefraction prior to weighing and blending with the second granule fractionand extragranular magnesium stearate. The two granule fractions weremixed for 10 min at 25 rpm before extragranular magnesium stearate wasmixed with the two granule fractions for additional 2 minutes at 25 rpmprior to the tabletting process. Tablets were prepared as described inthe section General Methods of Preparation.

The mixing time prior to granulation of the first granule fraction foreach experiment is shown in Table 7.

TABLE 7 Preparation of the first granule fraction Exp. Exp. Exp. Exp.Exp. Exp. V VI VII VIII IX X Composition type D D D E E E First mixingtime¹ (min) 75 20 50 50 50 50 Second mixing time² (min) 25 5 20 Totalmixing time of 75 20 50 75 55 70 intragranular lubricant (min) ¹Thefirst mixing time is the mixing time of enhancer and lubricant only.²The second mixing time is the mixing time of enhancer/lubricant blendand microcrystalline cellulose.

The first granule fractions were characterised by laser diffraction asdescribed in the section General Methods of Detection andCharacterisation. The results are shown in Tables 8-13 as a function ofthe roller compaction force used to prepare the first granule fraction.

TABLE 8 Particle sizes of the first granule fraction for experiment V(mixing time of 75 min prior to granulation) determined by laserdiffraction and shown as a function of the roller compaction force.Volume in % (v/v) Exp. V Size (μm) 4 kN/cm 7 kN/cm 10 kN/cm 13 kN/cm0.011 0.00 0.00 0.00 0.00 0.013 0.00 0.00 0.00 0.00 0.015 0.00 0.00 0.000.00 0.017 0.00 0.00 0.00 0.00 0.020 0.00 0.00 0.00 0.00 0.023 0.00 0.000.00 0.00 0.026 0.00 0.00 0.00 0.00 0.030 0.00 0.00 0.00 0.00 0.035 0.000.00 0.00 0.00 0.040 0.00 0.00 0.00 0.00 0.046 0.00 0.00 0.00 0.00 0.0520.00 0.00 0.00 0.00 0.060 0.00 0.00 0.00 0.00 0.069 0.00 0.00 0.00 0.000.079 0.00 0.00 0.00 0.00 0.091 0.00 0.00 0.00 0.00 0.105 0.00 0.00 0.000.00 0.120 0.00 0.00 0.00 0.00 0.138 0.00 0.00 0.00 0.00 0.158 0.00 0.000.00 0.00 0.182 0.00 0.00 0.00 0.00 0.209 0.00 0.00 0.00 0.00 0.240 0.000.00 0.00 0.00 0.275 0.00 0.00 0.00 0.00 0.316 0.00 0.00 0.00 0.00 0.3630.00 0.00 0.00 0.00 0.417 0.00 0.00 0.00 0.00 0.479 0.00 0.00 0.00 0.000.550 0.02 0.00 0.00 0.00 0.631 0.09 0.05 0.00 0.05 0.724 0.15 0.12 0.020.13 0.832 0.24 0.23 0.07 0.23 0.955 0.34 0.33 0.11 0.33 1.096 0.47 0.460.16 0.45 1.259 0.63 0.60 0.19 0.59 1.445 0.81 0.76 0.25 0.73 1.660 1.030.93 0.41 0.90 1.905 1.27 1.11 0.54 1.07 2.188 1.53 1.30 0.66 1.24 2.5121.80 1.47 0.76 1.40 2.884 2.07 1.63 0.84 1.55 3.311 2.31 1.76 0.89 1.683.802 2.51 1.86 0.92 1.77 4.365 2.65 1.91 0.93 1.83 5.012 2.71 1.91 0.921.84 5.754 2.67 1.86 0.89 1.80 6.607 2.56 1.77 0.84 1.72 7.586 2.35 1.630.79 1.60 8.710 2.09 1.46 0.74 1.45 10.000 1.78 1.27 0.68 1.28 11.4821.47 1.08 0.63 1.11 13.183 1.16 0.90 0.59 0.95 15.136 0.89 0.76 0.570.82 17.378 0.68 0.66 0.56 0.73 19.953 0.55 0.61 0.57 0.68 22.909 0.480.61 0.61 0.69 26.303 0.47 0.65 0.68 0.73 30.200 0.50 0.73 0.76 0.8034.674 0.55 0.82 0.85 0.89 39.811 0.62 0.93 0.96 0.98 45.709 0.69 1.051.08 1.06 52.481 0.76 1.18 1.20 1.15 60.256 0.84 1.33 1.35 1.24 69.1830.94 1.49 1.52 1.34 79.433 1.06 1.68 1.71 1.48 91.201 1.23 1.91 1.951.66 104.713 1.44 2.18 2.24 1.87 120.226 1.69 2.48 2.57 2.12 138.0381.99 2.84 2.97 2.39 158.489 2.31 3.24 3.42 2.67 181.970 2.63 3.69 3.922.96 208.930 2.92 4.16 4.44 3.23 239.883 3.15 4.63 4.95 3.50 275.4233.30 5.03 5.37 3.74 316.228 3.36 5.31 5.67 3.93 363.078 3.32 5.37 5.754.05 416.869 3.20 5.16 5.60 4.06 478.630 3.04 4.63 5.21 3.96 549.5412.90 3.80 4.62 3.75 630.957 2.81 2.76 3.92 3.45 724.436 2.80 1.63 3.213.11 831.764 2.83 0.80 2.57 2.75 954.993 2.84 0.60 2.04 2.39 1096.4782.74 0.40 1.61 2.02 1258.925 2.44 0.25 1.24 1.73 1445.440 1.94 0.14 0.881.39 1659.570 1.14 0.07 0.49 0.82 1905.461 0.28 0.01 0.12 0.20 2187.7620.00 0.00 0.00 0.00 2511.886 0.00 0.00 0.00 0.00 2884.032 0.00 0.00 0.000.00 3311.311 0.00 0.00 0.00 0.00 3801.894 0.00 0.00 0.00 0.00 4365.1580.00 0.00 0.00 0.00 5011.872 0.00 0.00 0.00 0.00 5754.399 0.00 0.00 0.000.00 6606.934 0.00 0.00 0.00 0.00 7585.776 0.00 0.00 0.00 0.00 8709.6360.00 0.00 0.00 0.00 10000.000 0.00 0.00 0.00 0.00

TABLE 9 Particle sizes of the first granule fraction for experiment VI(mixing time of 20 min prior to granulation) determined by laserdiffraction and shown as a function of the roller compaction force.Volume in % (v/v) Exp. VI Size (μm) 4 kN/cm 7 kN/cm 10 kN/cm 13 kN/cm0.011 0.00 0.00 0.00 0.00 0.013 0.00 0.00 0.00 0.00 0.015 0.00 0.00 0.000.00 0.017 0.00 0.00 0.00 0.00 0.020 0.00 0.00 0.00 0.00 0.023 0.00 0.000.00 0.00 0.026 0.00 0.00 0.00 0.00 0.030 0.00 0.00 0.00 0.00 0.035 0.000.00 0.00 0.00 0.040 0.00 0.00 0.00 0.00 0.046 0.00 0.00 0.00 0.00 0.0520.00 0.00 0.00 0.00 0.060 0.00 0.00 0.00 0.00 0.069 0.00 0.00 0.00 0.000.079 0.00 0.00 0.00 0.00 0.091 0.00 0.00 0.00 0.00 0.105 0.00 0.00 0.000.00 0.120 0.00 0.00 0.00 0.00 0.138 0.00 0.00 0.00 0.00 0.158 0.00 0.000.00 0.00 0.182 0.00 0.00 0.00 0.00 0.209 0.00 0.00 0.00 0.00 0.240 0.000.00 0.00 0.00 0.275 0.00 0.00 0.00 0.00 0.316 0.00 0.00 0.00 0.00 0.3630.00 0.00 0.00 0.00 0.417 0.00 0.00 0.00 0.00 0.479 0.00 0.00 0.00 0.000.550 0.00 0.00 0.00 0.00 0.631 0.07 0.05 0.00 0.00 0.724 0.17 0.12 0.020.02 0.832 0.30 0.22 0.07 0.06 0.955 0.43 0.30 0.10 0.10 1.096 0.59 0.390.15 0.14 1.259 0.77 0.49 0.18 0.17 1.445 0.97 0.59 0.23 0.21 1.660 1.190.69 0.37 0.33 1.905 1.43 0.80 0.50 0.44 2.188 1.67 0.90 0.61 0.53 2.5121.92 1.00 0.70 0.61 2.884 2.14 1.08 0.77 0.68 3.311 2.33 1.15 0.82 0.733.802 2.48 1.20 0.85 0.76 4.365 2.55 1.23 0.85 0.77 5.012 2.55 1.23 0.840.77 5.754 2.47 1.20 0.82 0.76 6.607 2.32 1.15 0.79 0.74 7.586 2.10 1.070.75 0.71 8.710 1.84 0.98 0.70 0.68 10.000 1.55 0.87 0.67 0.65 11.4821.27 0.77 0.63 0.62 13.183 1.01 0.67 0.61 0.61 15.136 0.80 0.60 0.600.60 17.378 0.66 0.56 0.61 0.62 19.953 0.58 0.55 0.64 0.65 22.909 0.560.58 0.69 0.70 26.303 0.59 0.63 0.76 0.78 30.200 0.65 0.71 0.85 0.8734.674 0.73 0.81 0.95 0.98 39.811 0.82 0.92 1.07 1.10 45.709 0.92 1.031.21 1.24 52.481 1.03 1.16 1.36 1.39 60.256 1.15 1.30 1.54 1.55 69.1831.30 1.46 1.73 1.74 79.433 1.49 1.65 1.96 1.95 91.201 1.71 1.88 2.212.18 104.713 1.98 2.17 2.51 2.46 120.226 2.30 2.51 2.86 2.77 138.0382.65 2.93 3.26 3.13 158.489 3.03 3.42 3.70 3.54 181.970 3.42 3.96 4.224.01 208.930 3.80 4.52 4.76 4.50 239.883 4.14 5.06 5.32 5.01 275.4234.38 5.51 5.82 5.47 316.228 4.49 5.80 6.20 5.81 363.078 4.43 5.85 6.355.95 416.869 4.16 5.63 6.21 5.83 478.630 3.70 5.14 5.74 5.43 549.5413.09 4.42 4.96 4.78 630.957 2.40 3.57 3.96 3.96 724.436 1.70 2.70 2.863.10 831.764 1.08 1.91 1.81 2.31 954.993 0.66 1.28 0.92 1.66 1096.4780.54 0.80 0.26 1.16 1258.925 0.42 0.47 0.08 0.79 1445.440 0.31 0.24 0.010.52 1659.570 0.16 0.11 0.00 0.27 1905.461 0.04 0.03 0.00 0.06 2187.7620.00 0.00 0.00 0.00 2511.886 0.00 0.00 0.00 0.00 2884.032 0.00 0.00 0.000.00 3311.311 0.00 0.00 0.00 0.00 3801.894 0.00 0.00 0.00 0.00 4365.1580.00 0.00 0.00 0.00 5011.872 0.00 0.00 0.00 0.00 5754.399 0.00 0.00 0.000.00 6606.934 0.00 0.00 0.00 0.00 7585.776 0.00 0.00 0.00 0.00 8709.6360.00 0.00 0.00 0.00 10000.000 0.00 0.00 0.00 0.00

TABLE 10 Particle sizes of the first granule fraction for experiment VII(mixing time of 50 min prior to granulation) determined by laserdiffraction and shown as a function of the roller compaction force.Volume in % (v/v) Exp. VII Size (μm) 4 kN/cm 7 kN/cm 10 kN/cm 0.011 0.000.00 0.00 0.013 0.00 0.00 0.00 0.015 0.00 0.00 0.00 0.017 0.00 0.00 0.000.020 0.00 0.00 0.00 0.023 0.00 0.00 0.00 0.026 0.00 0.00 0.00 0.0300.00 0.00 0.00 0.035 0.00 0.00 0.00 0.040 0.00 0.00 0.00 0.046 0.00 0.000.00 0.052 0.00 0.00 0.00 0.060 0.00 0.00 0.00 0.069 0.00 0.00 0.000.079 0.00 0.00 0.00 0.091 0.00 0.00 0.00 0.105 0.00 0.00 0.00 0.1200.00 0.00 0.00 0.138 0.00 0.00 0.00 0.158 0.00 0.00 0.00 0.182 0.00 0.000.00 0.209 0.00 0.00 0.00 0.240 0.00 0.00 0.00 0.275 0.00 0.00 0.000.316 0.00 0.00 0.00 0.363 0.00 0.00 0.00 0.417 0.00 0.00 0.00 0.4790.00 0.00 0.00 0.550 0.00 0.00 0.00 0.631 0.07 0.03 0.00 0.724 0.17 0.100.02 0.832 0.30 0.22 0.07 0.955 0.43 0.32 0.10 1.096 0.59 0.43 0.151.259 0.76 0.54 0.18 1.445 0.95 0.66 0.23 1.660 1.16 0.78 0.38 1.9051.39 0.89 0.51 2.188 1.63 1.00 0.63 2.512 1.86 1.10 0.72 2.884 2.07 1.190.79 3.311 2.25 1.26 0.84 3.802 2.39 1.30 0.87 4.365 2.46 1.32 0.885.012 2.46 1.32 0.87 5.754 2.38 1.28 0.84 6.607 2.24 1.22 0.81 7.5862.02 1.14 0.77 8.710 1.77 1.05 0.74 10.000 1.49 0.95 0.70 11.482 1.220.85 0.67 13.183 0.96 0.76 0.65 15.136 0.76 0.70 0.64 17.378 0.62 0.660.65 19.953 0.54 0.66 0.69 22.909 0.52 0.69 0.74 26.303 0.55 0.75 0.8230.200 0.62 0.84 0.92 34.674 0.70 0.95 1.03 39.811 0.79 1.07 1.16 45.7090.88 1.21 1.30 52.481 0.99 1.36 1.46 60.256 1.10 1.53 1.64 69.183 1.241.72 1.84 79.433 1.41 1.94 2.08 91.201 1.63 2.20 2.36 104.713 1.90 2.512.69 120.226 2.21 2.86 3.07 138.038 2.57 3.26 3.50 158.489 2.94 3.713.97 181.970 3.33 4.21 4.46 208.930 3.69 4.71 4.95 239.883 3.98 5.205.39 275.423 4.17 5.60 5.73 316.228 4.22 5.84 5.90 363.078 4.10 5.855.85 416.869 3.82 5.56 5.55 478.630 3.40 4.95 5.00 549.541 2.91 4.064.25 630.957 2.41 2.98 3.39 724.436 1.98 1.86 2.51 831.764 1.64 0.751.72 954.993 1.39 0.10 1.07 1096.478 1.23 0.00 0.59 1258.925 1.12 0.000.32 1445.440 0.91 0.00 0.20 1659.570 0.54 0.00 0.10 1905.461 0.13 0.000.03 2187.762 0.00 0.00 0.00 2511.886 0.00 0.00 0.00 2884.032 0.00 0.000.00 3311.311 0.00 0.00 0.00 3801.894 0.00 0.00 0.00 4365.158 0.00 0.000.00 5011.872 0.00 0.00 0.00 5754.399 0.00 0.00 0.00 6606.934 0.00 0.000.00 7585.776 0.00 0.00 0.00 8709.636 0.00 0.00 0.00 10000.000 0.00 0.000.00

TABLE 11 Particle sizes of the first granule fraction for experimentVIII (mixing time of 75 min prior to granulation) determined by laserdiffraction and shown as a function of the roller compaction force.Volume in % (v/v) Exp. VIII Size (μm) 4 kN/cm 7 kN/cm 10 kN/cm 13 kN/cm0.011 0.00 0.00 0.00 0.00 0.013 0.00 0.00 0.00 0.00 0.015 0.00 0.00 0.000.00 0.017 0.00 0.00 0.00 0.00 0.020 0.00 0.00 0.00 0.00 0.023 0.00 0.000.00 0.00 0.026 0.00 0.00 0.00 0.00 0.030 0.00 0.00 0.00 0.00 0.035 0.000.00 0.00 0.00 0.040 0.00 0.00 0.00 0.00 0.046 0.00 0.00 0.00 0.00 0.0520.00 0.00 0.00 0.00 0.060 0.00 0.00 0.00 0.00 0.069 0.00 0.00 0.00 0.000.079 0.00 0.00 0.00 0.00 0.091 0.00 0.00 0.00 0.00 0.105 0.00 0.00 0.000.00 0.120 0.00 0.00 0.00 0.00 0.138 0.00 0.00 0.00 0.00 0.158 0.00 0.000.00 0.00 0.182 0.00 0.00 0.00 0.00 0.209 0.00 0.00 0.00 0.00 0.240 0.000.00 0.00 0.00 0.275 0.00 0.00 0.00 0.00 0.316 0.00 0.00 0.00 0.00 0.3630.00 0.00 0.00 0.00 0.417 0.00 0.00 0.00 0.00 0.479 0.00 0.00 0.00 0.000.550 0.00 0.00 0.00 0.00 0.631 0.07 0.06 0.02 0.01 0.724 0.18 0.13 0.060.08 0.832 0.31 0.23 0.09 0.14 0.955 0.44 0.32 0.13 0.23 1.096 0.59 0.430.16 0.30 1.259 0.75 0.54 0.20 0.39 1.445 0.93 0.65 0.25 0.47 1.660 1.130.77 0.40 0.56 1.905 1.33 0.89 0.53 0.65 2.188 1.54 1.01 0.65 0.73 2.5121.75 1.12 0.75 0.81 2.884 1.93 1.22 0.83 0.89 3.311 2.09 1.30 0.89 0.953.802 2.20 1.35 0.92 0.99 4.365 2.26 1.38 0.93 1.02 5.012 2.25 1.38 0.921.04 5.754 2.18 1.35 0.89 1.03 6.607 2.06 1.30 0.86 1.00 7.586 1.88 1.220.81 0.96 8.710 1.67 1.13 0.77 0.90 10.000 1.45 1.04 0.73 0.84 11.4821.25 0.96 0.71 0.78 13.183 1.07 0.89 0.69 0.74 15.136 0.94 0.86 0.700.72 17.378 0.88 0.87 0.73 0.74 19.953 0.88 0.92 0.79 0.78 22.909 0.951.02 0.87 0.86 26.303 1.08 1.15 0.97 0.97 30.200 1.23 1.31 1.10 1.1034.674 1.41 1.47 1.24 1.23 39.811 1.57 1.63 1.38 1.36 45.709 1.73 1.771.53 1.48 52.481 1.86 1.90 1.67 1.59 60.256 1.96 2.00 1.81 1.69 69.1832.04 2.10 1.93 1.78 79.433 2.10 2.18 2.05 1.87 91.201 2.16 2.28 2.181.96 104.713 2.23 2.39 2.31 2.06 120.226 2.32 2.55 2.48 2.20 138.0382.45 2.75 2.70 2.39 158.489 2.62 3.02 3.00 2.65 181.970 2.85 3.35 3.423.02 208.930 3.11 3.74 3.94 3.50 239.883 3.41 4.18 4.57 4.09 275.4233.69 4.60 5.22 4.73 316.228 3.91 4.95 5.82 5.34 363.078 4.00 5.13 6.235.80 416.869 3.91 5.07 6.33 6.00 478.630 3.60 4.72 6.02 5.85 549.5413.09 4.08 5.28 5.33 630.957 2.43 3.21 4.20 4.50 724.436 1.68 2.24 2.873.49 831.764 0.98 1.28 1.60 2.45 954.993 0.58 0.47 0.90 1.52 1096.4780.44 0.13 0.53 0.80 1258.925 0.31 0.00 0.28 0.35 1445.440 0.21 0.00 0.110.19 1659.570 0.10 0.00 0.01 0.08 1905.461 0.03 0.00 0.00 0.02 2187.7620.00 0.00 0.00 0.00 2511.886 0.00 0.00 0.00 0.00 2884.032 0.00 0.00 0.000.00 3311.311 0.00 0.00 0.00 0.00 3801.894 0.00 0.00 0.00 0.00 4365.1580.00 0.00 0.00 0.00 5011.872 0.00 0.00 0.00 0.00 5754.399 0.00 0.00 0.000.00 6606.934 0.00 0.00 0.00 0.00 7585.776 0.00 0.00 0.00 0.00 8709.6360.00 0.00 0.00 0.00 10000.000 0.00 0.00 0.00 0.00

TABLE 12 Particle sizes of the first granule fraction for experiment IX(mixing time of 55 min prior to granulation) determined by laserdiffraction and shown as a function of the roller compaction force.Volume in % (v/v) Exp. IX Size (μm) 4 kN/cm 7 kN/cm 10 kN/cm 13 kN/cm0.011 0.00 0.00 0.00 0.00 0.013 0.00 0.00 0.00 0.00 0.015 0.00 0.00 0.000.00 0.017 0.00 0.00 0.00 0.00 0.020 0.00 0.00 0.00 0.00 0.023 0.00 0.000.00 0.00 0.026 0.00 0.00 0.00 0.00 0.030 0.00 0.00 0.00 0.00 0.035 0.000.00 0.00 0.00 0.040 0.00 0.00 0.00 0.00 0.046 0.00 0.00 0.00 0.00 0.0520.00 0.00 0.00 0.00 0.060 0.00 0.00 0.00 0.00 0.069 0.00 0.00 0.00 0.000.079 0.00 0.00 0.00 0.00 0.091 0.00 0.00 0.00 0.00 0.105 0.00 0.00 0.000.00 0.120 0.00 0.00 0.00 0.00 0.138 0.00 0.00 0.00 0.00 0.158 0.00 0.000.00 0.00 0.182 0.00 0.00 0.00 0.00 0.209 0.00 0.00 0.00 0.00 0.240 0.000.00 0.00 0.00 0.275 0.00 0.00 0.00 0.00 0.316 0.00 0.00 0.00 0.00 0.3630.00 0.00 0.00 0.00 0.417 0.00 0.00 0.00 0.00 0.479 0.00 0.00 0.00 0.000.550 0.00 0.00 0.00 0.00 0.631 0.06 0.05 0.00 0.00 0.724 0.15 0.12 0.050.02 0.832 0.27 0.21 0.13 0.06 0.955 0.38 0.29 0.23 0.09 1.096 0.53 0.370.31 0.13 1.259 0.69 0.47 0.40 0.15 1.445 0.86 0.56 0.48 0.20 1.660 1.060.65 0.56 0.33 1.905 1.26 0.75 0.63 0.44 2.188 1.47 0.84 0.70 0.54 2.5121.67 0.93 0.76 0.63 2.884 1.86 1.00 0.81 0.70 3.311 2.01 1.06 0.85 0.753.802 2.12 1.10 0.89 0.78 4.365 2.18 1.13 0.90 0.79 5.012 2.18 1.13 0.910.79 5.754 2.11 1.11 0.90 0.78 6.607 1.98 1.07 0.88 0.76 7.586 1.81 1.020.85 0.73 8.710 1.60 0.95 0.81 0.69 10.000 1.38 0.89 0.77 0.66 11.4821.18 0.83 0.74 0.64 13.183 1.01 0.78 0.71 0.63 15.136 0.89 0.76 0.710.63 17.378 0.83 0.77 0.73 0.66 19.953 0.84 0.82 0.78 0.70 22.909 0.920.90 0.86 0.78 26.303 1.05 1.02 0.96 0.87 30.200 1.21 1.16 1.09 0.9834.674 1.39 1.31 1.22 1.11 39.811 1.56 1.47 1.36 1.25 45.709 1.72 1.631.50 1.39 52.481 1.86 1.77 1.64 1.54 60.256 1.98 1.91 1.77 1.69 69.1832.07 2.04 1.88 1.83 79.433 2.15 2.16 2.00 1.98 91.201 2.22 2.28 2.112.12 104.713 2.32 2.43 2.24 2.27 120.226 2.44 2.60 2.39 2.44 138.0382.60 2.83 2.60 2.66 158.489 2.80 3.13 2.90 2.94 181.970 3.05 3.52 3.313.33 208.930 3.33 4.01 3.84 3.82 239.883 3.62 4.58 4.48 4.44 275.4233.87 5.16 5.16 5.12 316.228 4.03 5.67 5.80 5.78 363.078 4.05 5.98 6.246.29 416.869 3.90 5.98 6.38 6.53 478.630 3.56 5.57 6.11 6.39 549.5413.06 4.75 5.41 5.83 630.957 2.44 3.56 4.38 4.90 724.436 1.79 2.19 3.133.74 831.764 1.18 0.73 1.87 2.52 954.993 0.66 0.00 0.75 1.42 1096.4780.33 0.00 0.12 0.56 1258.925 0.22 0.00 0.00 0.19 1445.440 0.14 0.00 0.000.02 1659.570 0.07 0.00 0.00 0.00 1905.461 0.02 0.00 0.00 0.00 2187.7620.00 0.00 0.00 0.00 2511.886 0.00 0.00 0.00 0.00 2884.032 0.00 0.00 0.000.00 3311.311 0.00 0.00 0.00 0.00 3801.894 0.00 0.00 0.00 0.00 4365.1580.00 0.00 0.00 0.00 5011.872 0.00 0.00 0.00 0.00 5754.399 0.00 0.00 0.000.00 6606.934 0.00 0.00 0.00 0.00 7585.776 0.00 0.00 0.00 0.00 8709.6360.00 0.00 0.00 0.00 10000.000 0.00 0.00 0.00 0.00

TABLE 13 Particle sizes of the first granule fraction for experiment X(mixing time of 70 min prior to granulation) determined by laserdiffraction and shown as a function of the roller compaction force.Volume in % (v/v) Exp. X Size (μm) 4 kN/cm 7 kN/cm 10 kN/cm 0.011 0.000.00 0.00 0.013 0.00 0.00 0.00 0.015 0.00 0.00 0.00 0.017 0.00 0.00 0.000.020 0.00 0.00 0.00 0.023 0.00 0.00 0.00 0.026 0.00 0.00 0.00 0.0300.00 0.00 0.00 0.035 0.00 0.00 0.00 0.040 0.00 0.00 0.00 0.046 0.00 0.000.00 0.052 0.00 0.00 0.00 0.060 0.00 0.00 0.00 0.069 0.00 0.00 0.000.079 0.00 0.00 0.00 0.091 0.00 0.00 0.00 0.105 0.00 0.00 0.00 0.1200.00 0.00 0.00 0.138 0.00 0.00 0.00 0.158 0.00 0.00 0.00 0.182 0.00 0.000.00 0.209 0.00 0.00 0.00 0.240 0.00 0.00 0.00 0.275 0.00 0.00 0.000.316 0.00 0.00 0.00 0.363 0.00 0.00 0.00 0.417 0.00 0.00 0.00 0.4790.00 0.00 0.00 0.550 0.00 0.00 0.00 0.631 0.07 0.05 0.00 0.724 0.16 0.110.00 0.832 0.28 0.19 0.00 0.955 0.40 0.26 0.00 1.096 0.54 0.34 0.001.259 0.70 0.43 0.00 1.445 0.88 0.52 0.01 1.660 1.06 0.61 0.12 1.9051.26 0.69 0.30 2.188 1.46 0.78 0.45 2.512 1.65 0.86 0.58 2.884 1.82 0.940.67 3.311 1.96 1.00 0.74 3.802 2.06 1.04 0.77 4.365 2.10 1.07 0.775.012 2.09 1.08 0.75 5.754 2.02 1.06 0.71 6.607 1.89 1.03 0.66 7.5861.73 0.99 0.62 8.710 1.54 0.93 0.58 10.000 1.35 0.87 0.55 11.482 1.180.81 0.54 13.183 1.03 0.77 0.54 15.136 0.93 0.74 0.56 17.378 0.89 0.750.60 19.953 0.92 0.78 0.65 22.909 1.00 0.85 0.71 26.303 1.12 0.95 0.7930.200 1.28 1.08 0.89 34.674 1.46 1.22 1.00 39.811 1.63 1.37 1.13 45.7091.78 1.52 1.26 52.481 1.91 1.67 1.39 60.256 2.02 1.80 1.52 69.183 2.091.92 1.64 79.433 2.15 2.03 1.76 91.201 2.20 2.14 1.87 104.713 2.27 2.262.01 120.226 2.36 2.43 2.18 138.038 2.49 2.65 2.42 158.489 2.66 2.962.74 181.970 2.87 3.36 3.20 208.930 3.10 3.84 3.77 239.883 3.31 4.364.45 275.423 3.47 4.86 5.18 316.228 3.54 5.24 5.87 363.078 3.46 5.426.40 416.869 3.25 5.34 6.66 478.630 2.91 4.97 6.55 549.541 2.50 4.356.07 630.957 2.10 3.58 5.27 724.436 1.77 2.78 4.26 831.764 1.54 2.073.19 954.993 1.39 1.50 2.18 1096.478 1.39 1.08 1.32 1258.925 1.26 0.780.68 1445.440 1.01 0.54 0.33 1659.570 0.60 0.29 0.13 1905.461 0.14 0.070.03 2187.762 0.00 0.00 0.00 2511.886 0.00 0.00 0.00 2884.032 0.00 0.000.00 3311.311 0.00 0.00 0.00 3801.894 0.00 0.00 0.00 4365.158 0.00 0.000.00 5011.872 0.00 0.00 0.00 5754.399 0.00 0.00 0.00 6606.934 0.00 0.000.00 7585.776 0.00 0.00 0.00 8709.636 0.00 0.00 0.00 10000.000 0.00 0.000.00

The tablet resistance to crushing was determined as described in thesection General Methods of Detection and Characterisation. The resultsare shown in Tables 14-17 as a function of the compression force used toprepare the tablets and as a function of the roller compaction forceused to prepare the first granule fraction.

TABLE 14 Tablet resistance to crushing as a function of the compressionforce for experiment V and the applied roller compaction force for thefirst granule fraction (mixing time of 75 minutes prior to granulation,Composition Type D). Exp. V - 4 kN/cm Exp. V - 7 kN/cm Exp. V - 13 kN/cmTablet Tablet Tablet Compression resistance to Compression resistance toCompression resistance to force (kN) crushing (N) force (kN) crushing(N) force (kN) crushing (N) 2.7 32 2.5 27 2.3 18 3.6 44 4.4 48 3.4 285.5 72 6.1 68 5.2 45 7.8 100 8.4 89 6.9 64 9.3 118 10.2 107 8.9 84 10.2128 11.7 120 10.7 94 10.8 132 13.2 135 11.7 99 11.8 143 — — 13.6 10812.9 149 — — — —

TABLE 15 Tablet resistance to crushing as a function of the compressionforce for experiment VI and the applied roller compaction force for thefirst granule fraction (mixing time of 20 min prior to granulation,Composition Type D). Exp. VI - 4 kN/cm Exp. VI - 7 kN/cm Exp. VI - 13kN/cm Tablet Tablet Tablet Compression resistance to Compressionresistance to Compression resistance to force (kN) crushing (N) force(kN) crushing (N) force (kN) crushing (N) 3.0 41 2.8 27 3.0 16 4.2 563.4 36 4.3 25 5.3 72 4.7 54 5.9 34 6.6 90 5.8 63 8.2 49 8.2 106 7.1 839.8 57 10.6 134 9.1 102 11.6 64 12.0 146 10.3 113 12.8 70 13.3 152 11.5125 13.5 72 — — 13.4 134 — —

TABLE 16 Tablet resistance to crushing as a function of the compressionforce for experiment VIII and the applied roller compaction force forthe first granule fraction (mixing time of 75 min prior to granulation,Composition Type E). Exp. VIII - 7 kN/cm Exp. VIII - 13 kN/cm Exp.VIII - 4 kN/cm Tablet Tablet Tablet resistance resistance Compressionresistance to Compression to crushing Compression to crushing force (kN)crushing (N) force (kN) (N) force (kN) (N) 2.9 43 2.4 26 2.7 21 3.8 543.4 37 3.9 32 4.6 70 4.4 51 5.2 47 5.5 83 5.8 67 7.5 67 7.0 105 7.9 9410.2 86 8.2 123 10.4 117 12.2 96 10.2 145 12.2 124 13.4 103 11.8 15812.9 132 — — 13.4 165 14.0 138 — —

TABLE 17 Tablet resistance to crushing as a function of the compressionforce for experiment IX and the applied roller compaction force for thefirst granule fraction (mixing time of 55 min prior to granulation,Composition Type E). Exp. IX - 4 kN/cm Exp. IX - 7 kN/cm Exp. IX - 13kN/cm Tablet Tablet Tablet resistance resistance resistance Compressionto crushing Compression to crushing Compression to crushing force (kN)(N) force (kN) (N) force (kN) (N) 2.9 41 3.0 31 3.0 18 4.0 59 4.0 41 4.027 5.2 80 4.9 51 5.6 41 6.6 99 6.9 79 7.6 55 8.5 126 9.4 94 10.4 74 10.5146 11.2 119 11.9 81 12.2 163 13.1 135 14.1 91 14.0 172 — — — — — — — —— —

The tablet friability was determined as described in the section GeneralMethods of Detection and Characterisation. The results are shown inTables 18-21 as a function of the compression force used to prepare thetablets and as a function of the roller compaction force used to preparethe first granule fraction.

TABLE 18 Tablet friability as a function of the compression force forexperiment V and the applied roller compaction force for the firstgranule fraction (mixing time of 75 min prior to granulation prior togranulation, Composition Type D). Exp. V - 4 kN/cm Exp. V - 7 kN/cm Exp.V - 13 kN/cm Com- Tablet Tablet Com- Tablet pression friabilityCompression friability pression friability force (kN) (% (w/w)) force(kN) (% (w/w)) force (kN) (% (w/w)) 2.7 0.82 2.5 1.73 2.3 100.0 3.6 0.393.4 0.56 3.4 1.67 5.5 0.14 4.4 0.32 5.2 0.30 7.8 0.18 6.1 0.16 6.9 0.23— — — — 8.9 0.14 — — — — 11.7 0.15

TABLE 19 Tablet friability as a function of the compression force forexperiment VI and the applied roller compaction force for the firstgranule fraction (mixing time of 20 min prior to granulation,Composition Type D). Exp. VI - 4 kN/cm Exp. VI - 13 kN/cm CompressionTablet Compression Tablet force friability force friability (kN) (%(w/w)) (kN) (% (w/w)) 3.0 0.46 3.0 100.0 4.2 0.26 4.3 8.91 5.3 0.16 5.90.62 6.6 0.12 8.2 0.36 — — 9.8 0.24 — — 11.6 0.21

TABLE 20 Tablet friability as a function of the compression force forexperiment VIII and the applied roller compaction force for the firstgranule fraction (mixing time of 75 minutes prior to granulation,Composition Type E). Exp. VIII - 4 kN/cm Exp. VIII - 7 kN/cm Exp. VIII -13 kN/cm Com- Tablet Tablet Com- Tablet pression friability Compressionfriability pression friability force (kN) (% (w/w)) force (kN) (% (w/w))force (kN) (% (w/w)) 2.9 0.23 2.4 1.25 2.7 3.10 3.8 0.17 3.4 0.45 3.90.54 4.6 0.11 4.4 0.25 5.2 0.11 5.5 — 5.8 0.17 7.5 0.05 7.0 — 7.9 — 10.2—

TABLE 21 Tablet friability as a function of the compression force forexperiment IX and the applied roller compaction force for the firstgranule fraction (mixing time of 55 minutes prior to granulation,Composition Type E). Exp. IX - 4 kN/cm Exp. IX - 7 kN/cm Exp. IX - 13kN/cm Com- Tablet Tablet Com- Tablet pression friability Compressionfriability pression friability force (kN) (% (w/w)) force (kN) (% (w/w))force (kN) (% (w/w)) 2.9 0.15 3.0 0.70 3.0 12.00 4.0 0.06 4.0 0.29 4.01.41 5.2 — 4.9 — 5.6 0.29 6.6 — 6.9 — 7.6 0.20 8.5 — 9.4 — 10.4 0.14

The tablet disintegration time was determined as described in thesection General Methods of Detection and Characterisation. The resultsare shown in Tables 22-23 as a function of the compression force used toprepare the tablets and as a function of the roller compaction forceused to prepare the first granule fraction.

TABLE 22 Tablet disintegration time as a function of the compressionforce for experiment VIII and the applied roller compaction force forthe first granule fraction (mixing time of 75 min prior to granulation,Composition Type E). Exp. VIII - 4 kN/cm Exp. VIII - 7 kN/cm Exp. VIII -13 kN/cm Tablet Tablet Tablet Compression disintegration Compressiondisintegration Compression disintegration force (kN) time (min) force(kN) time (min) force (kN) time (min) 2.9 9.4 2.4 7.4 2.7 7.2 3.8 9.93.4 7.6 3.9 8.5 4.6 10.6 4.4 8.9 5.2 9.4 5.5 11.0 5.8 9.6 7.5 10.3 7.08.7 7.9 10.3 10.2 10.4 8.2 9.1 10.4 11.2 12.2 11.7 10.2 9.3 12.2 11.813.4 10.9 11.8 9.6 12.9 11.2 — — 13.4 9.6 14.0 11.2 — —

TABLE 23 Tablet disintegration time as a function of the compressionforce for experiment IX and the applied roller compaction force for thefirst granule fraction (mixing time of 55 min prior to granulation,Composition Type E). Exp. IX - 4 kN/cm Exp. IX - 7 kN/cm Exp. IX - 13kN/cm Tablet Tablet Tablet Compression disintegration Compressiondisintegration Compression disintegration force (kN) time (min) force(kN) time (min) force (kN) time (min) 2.9 6.9 3.0 8.9 3.0 10.0 4.0 8.74.0 10.9 4.0 9.4 5.2 8.6 6.9 9.3 5.6 10.0 6.6 10.0 9.4 12.6 7.6 10.7 8.59.9 11.2 13.2 10.4 11.1 10.5 9.4 13.1 9.0 11.9 11.6 12.2 9.2 — — 14.111.6 14.0 8.5 — — — — — — — — — —

The results show that the pharmaceutical technical properties of thetablets prepared from Composition Type D were either unaltered orimproved when a longer mixing time prior to granulation was used to mixthe magnesium stearate and SNAC, i.e. the crushing strength of thetablets was increased or un-altered and the friability of the tabletswas unaltered or reduced. In addition, the time used for mixing of theblend of magnesium stearate and SNAC prior to granulation did notinfluence the size or the extent of granulation.

The results show that the pharmaceutical technical properties of thetablets prepared from Composition Type E were either unaltered orimproved when a longer mixing time prior to granulation was used to mixthe magnesium stearate, SNAC and microcrystalline cellulose, i.e. thecrushing strength of the tablets was increased or unaltered, thefriability of the tablets was unaltered or reduced, and thedisintegration time of the tablets was unaltered. In addition, the timeused for mixing of the blend of magnesium stearate, SNAC, andmicrocrystalline cellulose prior to granulation did not influence thesize or the extent of granulation.

While certain features of the invention have been illustrated anddescribed herein, many modifications, substitutions, changes, andequivalents will now occur to those of ordinary skill in the art. It is,therefore, to be understood that the appended claims are intended tocover all such modifications and changes as fall within the true spiritof the invention.

The invention claimed is:
 1. A process of producing by dry granulation agranule comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acidand a lubricant, wherein said process comprises: mixing said salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid and said lubricant for morethan 5 minutes, wherein the granule produced by said process does notcontain a pharmaceutically active agent.
 2. The process according toclaim 1, wherein the duration of said mixing is at least 20 minutes. 3.The process according to claim 1, wherein the amount of said lubricantis at least 0.25% (w/w) of said composition.
 4. The process according toclaim 1, wherein the amount of said lubricant is at least 2.0% (w/w) ofsaid composition.
 5. The process according to claim 4, wherein theamount of said lubricant is less than 10.0% (w/w) of said composition.6. The process according to claim 5, wherein the lubricant is magnesiumstearate.
 7. A process of producing by dry granulation a granulecomprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and alubricant, wherein said process comprises the steps: a) mixing said saltof N-(8-(2-hydroxybenzoyl)amino)caprylic acid and said lubricant formore than 5 minutes; and b) roller compacting the mixture of step a,wherein the granule produced by said process does not contain apharmaceutically active agent.
 8. The process according to claim 7,wherein the duration of said mixing in step a is at least 20 minutes. 9.The process according to claim 7, wherein the amount of said lubricantis at least 0.25% (w/w) of said composition.
 10. The process accordingto claim 9, wherein the amount of said lubricant is at least 2.0% (w/w)of said composition.
 11. The process according to claim 10, wherein theamount of said lubricant is less than 10.0% (w/w) of said composition.12. The process according to claim 11, wherein the lubricant ismagnesium stearate.